432 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2020 | Volume 89 | https://doi.org/10.6016/ZdravVestn.2934 1 Institute of Oncology Ljubljana, Ljubljana, Slovenia 2 Advanced heart failure and transplantation center, Department of Cardiology, Division of Internal Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia Correspondence/ Korespondenca: Gregor Poglajen, e: gregor. poglajen@kclj.si Key words: myocard injury; anthracyclins; heart failure prevention; heart failure treatment Ključne besede: poškodba miokarda; antraciklini; preprečevanje srčnega popuščanja; zdravljenje srčnega popuščanja Received: 25. 2. 2019 Accepted: 29. 4. 2020 eng slo element en article-lang 10.6016/ZdravVestn.2934 doi 25.2.2019 date-received 29.4.2020 date-accepted Cardiovascular system Srce in ožilje discipline Professional article Strokovni članek article-type Heart failure and oncologic treatment Srčno popuščanje in onkološko zdravljenje article-title Heart failure and oncologic treatment Srčno popuščanje in onkološko zdravljenje alt-title myocardial injury, anthracyclins, heart failure prevention, heart failure treatment poškodba miokarda, antraciklini, preprečevan- je srčnega popuščanja, zdravljenje srčnega popuščanja kwd-group The authors declare that there are no conflicts of interest present. Avtorji so izjavili, da ne obstajajo nobeni konkurenčni interesi. conflict year volume first month last month first page last page 2020 89 7 8 432 445 name surname aff email Gregor Poglajen 2 gregor.poglajen@kclj.si name surname aff Lučka Boltežar 1 eng slo aff-id Institute of Oncology Ljubljana, Ljubljana, Slovenia Onkološki inštitut Ljubljana, Ljubljana, Slovenija 1 Advanced heart failure and transplantation center, Department of Cardiology, Division of Internal Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia Program za napredovalo srčno popuščanje in transplantacije srca, Klinični oddelek za kardiologijo, Interna klinika, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija Heart failure and oncologic treatment Srčno popuščanje in onkološko zdravljenje Lučka Boltežar,1 Gregor Poglajen2 Abstract Heart failure after oncological treatment is a hot topic in oncology as well as in cardiology and it demands quick diagnostic and therapeutic interventions. The most commonly used classifica- tion of myocardial damage is still type I (anthracycline-like) and type II (trastuzumab-like) myo- cardial injury. Radiotherapy is also a significant contributor to cardiotoxicity in onco-logic pa- tients. The European Society of Cardiology has published guidelines regarding surveillance and follow up of such patients, the golden standard of imaging techniques being echocardiography. Other imaging techniques and laboratory modalities could be used but are not widely available. This year’s recommendations of the European Society of Medical Oncology advise considering the use of cardioprotective medications before and during therapy in individuals with known cardiovascular risk factors. However, individual approach to every patient is of paramount im- portance. Izvleček Srčno popuščanje po onkološkem zdravljenju je vse bolj aktualna tema, ki zahteva hitro obravnavo ter čimprejšnje zdravljenje. K nastanku močno prispevajo bolnikovi predobstoječi dejavniki. Vedno najpogosteje uporabljamo delitev poškodb miokarda na tip I (predstavniki so antraciklini) in tip II (glavni predstavnik je trastuzumab), svojstvena entiteta pa je tudi obsevalno zdravljenje. Evropsko združenje za kardiologijo je objavilo priporočila za presejanje in sleden- je onkoloških bolnikov. Glavna priporočena presejalna metoda pa je ehokardiografija. Uporaba ostalih slikovnih in laboratorijskih metod je odvisna od dostopnosti osnovne preiskave. Letošn- ja priporočila Evropskega združenja za internistično onkologijo prvič svetujejo uvajanje kardio- protektivnega zdravljenja pri ogroženi populaciji. Za doseganje optimalnih rezultatov zdravljenja pa je potrebna individualna obravnava vsakega bolnika. Cite as/Citirajte kot: Boltežar L, Poglajen G. Heart failure and oncologic treatment. Zdrav Vestn. 2020;89(7– 8):432–445. DOI: https://doi.org/10.6016/ZdravVestn.2934 Copyright (c) 2020 Slovenian Medical Journal. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Slovenian Medical Journal 1 Introduction In 2016, according to the Slovenian Cancer Registry, 15,072 patients were di- agnosed with cancer (1). The development of the profession and the pharmaceutical industry brings new and more demand- ing drugs into everyday clinical practice; drugs with adverse effects and mecha- nisms of action that are often not yet fully 433 PROFESSIONAL ARTICLE Heart failure and oncologic treatment defined. However, the adverse effects of oncological treatment on the cardiovas- cular system are an increasingly recog- nizable complication. They are important especially because of the growing popula- tion of patients with curable cancer. After a successful oncological treatment, the life expectancy of these patients is long, so so consequences of oncological treatment can have a significant negative impact. Ad- verse effects of oncological treatment can be divided into early and late according to the time of onset. In analysing the latter, the European Society of Cardiology (ESC) identified nine categories of cardiovascu- lar complications: myocardial dysfunction and heart failure, coronary heart disease, valvular disease, arrhythmias, arterial hypertension, thromboembolic disease, peripheral vascular disease, pulmonary hypertension, and pericardium-related complications (2). The heart failure syn- drome is considered to be one of the most important complications of oncological treatment in cancer patients, as it signifi- cantly increases the morbidity and mortal- ity rates of this group of patients. In this review article, we want to pres- ent the mechanisms of heart failure fol- lowing various forms of oncological treat- ment and present the possibilities of heart failure prevention and strategies for this treatment in oncological patients. 2 Mechanisms of heart failure in systemic cancer treatment and radiotherapy Cardiotoxic drugs are divided by the type of myocardial damage they cause and according to how long-lasting it is. Type I damage is associated with cell death and consequently with irreversible myocardial damage. This type of damage is most com- monly seen in anthracycline treatment. Type II damage, with trastuzumab as the main agent, is expected to be (at least par- tially) curable (2-4). In everyday clinical practice, however, the division into myo- cardial damage of types I and II is blurred, as patients are often treated with a combi- nation of chemotherapeutics, either con- currently or sequentially, with myocardial toxicity of these drugs likely to be syner- gistic (5). The general risk factors for the onset of cardiotoxicity are summarized in Table 1. Patients with a familial predispo- sition to cardiovascular disease, pre-exist- ing heart disease, and patients with an un- healthy lifestyle are the most susceptible to developing cardiotoxicity. 2.1 Type I myocardial injury Type I myocardial injury is most often represented by an anthracycline cardio- toxicity model. There are several proposed mechanisms for the development of an- thracycline cardiotoxicity. Anthracyclines bind to DNA, inhibit topoisomerase II-be- ta, leading to impairment of DNA repair mechanisms; they also impair protein syn- thesis and cause the release of free oxygen radicals. All of the listed effects can lead to cardiomyocyte apoptosis (5,7). Anth- racycline treatment therefore leads to a loss of cardiomyocyte mass, which makes its effects irreversible. Risk factors associ- ated with the development of anthracy- cline cardiotoxicity are: cumulative dose of anthracycline used, age below 18 years or over 65 years at the start of treatment, female sex, chronic kidney disease, any ir- radiation in the cardiac area, concomitant treatment with microtubule inhibitors, al- kylating agents, immunotherapy or target- ed therapy, and individual patient charac- teristics (certain genetic polymorphisms (8), arterial hypertension, pre-existing cardiovascular disease, diabetes, smoking, menopause, etc.) (2,5). Anthracycline car- diotoxicity can be acute, subacute, or late. Acute anthracycline cardiotoxicity is ex- tremely rare and is clinically mostly man- ifested by changes in ECG changes, su- praventricular arrhythmias, and transient left and/or right ventricular dysfunction. Subacute anthracycline cardiotoxicity typ- ically presents within the first 12 months 434 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2020 | Volume 89 | https://doi.org/10.6016/ZdravVestn.2934 above 150 mg/m2 and daunorubicin above 800 mg/m2 (2). Among other classic chemotherapeu- tics, cyclophosphamide, ifosfamide, pacl- itaxel, docetaxel, and cisplatin also cause heart failure, but all in much lower per- centages than anthracyclines (2,5). 2.2 Type II myocardial injury Trastuzumab is the most studied car- diotoxicity-related monoclonal antibody that binds to human epidermal growth factor receptor 2 (anti-HER2) and is used mostly, but not exclusively, in the treat- ment of breast cancer that has an overex- pressed HER2 receptor. Other anti-HER2 drugs currently in use in Slovenia are lapa- tinib (a tyrosine kinase inhibitor that also binds to the HER2 receptor), pertuzum- ab (an anti-HER2 antibody) and T-DM1 (an antibody-drug conjugate in which the cytotoxic substance emtansin (DM1) is bound to trastuzumab). HER2 receptors are also expressed on cardiomyocytes (5). The generally accepted putative mecha- nism of action of anti-HER2 drugs are the changes in the structure and function of Ta bl e 1: G en er al fa ct or s t ha t m ak e pa tie nt s m or e su sc ep tib le to d ev el op in g ca rd io to xi ci ty (2 ,6 ). LV – le ft ve nt ric le , P CI – p er cu ta ne ou s a ng io pl as ty , C AB G – Co ro na ry a rt er y by pa ss g ra fti ng . De m og ra ph ic fa ct or s Li fe st yl e fa ct or s Cu rr en t c ar di ol og ic al st at e Pr ev io us ca rd io to xi c th er ap y Ag e (p ae di at ric p op ul at io n < 18 y ea rs , a ge o ve r 65 y ea rs w ith a nt hr ac yc lin e tr ea tm en t a nd a ge ov er 5 0 ye ar s w ith T ra st uz um ab th er ap y) . Sm ok in g. He ar t f ai lu re (r eg ar dl es s o f L V ej ec tio n fra ct io n) . Pr ev io us a nt hr ac yc lin e tr ea tm en ts . Fa m ily h ist or y of e ar ly ca rd io va sc ul ar d is ea se (o ns et b ef or e ag e 50 ). O be si ty . As ym pt om at ic LV d ys fu nc tio n. Pr ev io us m ed ia st in al o r c he st w al l i rr ad ia tio n. Ar te ria l h yp er te ns io n. Ex ce ss iv e al co ho l c on su m pt io n. El ev at ed se ru m b io m ar ke r v al ue s b ef or e th e st ar t o f o nc ol og ic al tr ea tm en t. Di ab et es . Pr ed om in an tly se de nt ar y lif es ty le w ith ou t s uff ic ie nt ph ys ic al a ct iv ity . Co ro na ry h ea rt d is ea se (p rio r m yo ca rd ia l in fa rc tio n, a ng in a pe ct or is , c on di tio n fo llo w in g PC I o r C AB G) . Hy pe rc ho le st er ol em ia . M od er at e or se ve re va lv e fa ilu re w ith hy pe rt ro ph y or im pa ire d LV fu nc tio n. Hy pe rt en si ve h ea rt d is ea se w ith LV hy pe rt ro ph y. Ca rd io m yo pa th ie s: • ca rd ia c s ar co id os is w ith m yo ca rd ia l in vo lv em en t, • si gn ifi ca nt ca rd ia c a rr hy th m ia s ( e. g. , a tr ia l fib ril la tio n, v en tr ic ul ar ta ch yc ar di as ). Diagnostic method Current diagnostic criteria Echocardiography (3D estimate of LV ejection fraction, 2D estimate of LV ejection fraction according to Simpson, GLS) LVEF: decrease of 10 % below the lower limit of normal signifies cardiotoxicity. GLS: a relative decrease of > 12 % from the basal measurement indicates the possibility of cardiotoxicity or an absolute decrease of 5 %. Nuclear cardiac imaging (MUGA-multigated radionuclide angiography) A reduction of 10% of the LV ejection fraction to a value below 50 % signifies cardiotoxicity. Magnetic resonance imaging of the heart It is mostly a supplementary method when other techniques are not conclusive, or to confirm LV dysfunction at borderline pathological LVEF. Serum biomarkers (troponin I, high-sensitivity troponin I, BNP, NT-proBNP) An increase in troponin might help identify patients for whom the addition of an ACE inhibitor would be beneficial during treatment with anthracyclines. Routine use of BNP and NT-proBNP in the monitoring of high- risk patients requires further research. Table 2: Diagnostic methods for the detection of heart failure (summarized after (2) and (6)). LP - left ventricle, GLS - global longitudinal strain, LVEF - left ventricular ejection fraction, BNP - B-type natriuretic peptide, NT-proBNP - N-terminal segment of B-type natriuretic peptide, ACE - angiotensin-converting enzyme. 435 PROFESSIONAL ARTICLE Heart failure and oncologic treatment after initiation of anthracycline therapy, whereas late anthracycline cardiotoxicity manifests later. Clinically, it usually mani- fests as heart failure syndrome a few years after the end of treatment. There is no uniform definition for late anthracycline cardiotoxicity in the literature. Some au- thors identify it as early as in the first year following treatment (9), some set the me- dian at 7 years after treatment (2,10), and cardiotoxicity 20 years after treatment has also been described (10). If heart failure is detected early enough, progression can be relatively effectively slowed with ap- propriate treatment. However, in patients with a late form of anthracycline cardio- toxicity and an advanced heart failure, the response to treatment of heart failure is generally poor, which is why non-phar- macological forms of treatment for heart failure should be considered (11). Cumu- lative doses of anthracyclines are associat- ed with a higher risk of heart failure. Sig- nificant risk (probability of 5% or more) of developing heart failure after anthracy- cline treatment occurs with a cumulative dose of doxorubicin above 400 mg/m2, epirubicin above 900 mg/m2, idarubicin above 150 mg/m2 and daunorubicin above 800 mg/m2 (2). Among other classic chemotherapeu- tics, cyclophosphamide, ifosfamide, pacl- itaxel, docetaxel, and cisplatin also cause heart failure, but all in much lower per- centages than anthracyclines (2,5). 2.2 Type II myocardial injury Trastuzumab is the most studied car- diotoxicity-related monoclonal antibody that binds to human epidermal growth factor receptor 2 (anti-HER2) and is used mostly, but not exclusively, in the treat- ment of breast cancer that has an overex- pressed HER2 receptor. Other anti-HER2 drugs currently in use in Slovenia are lapa- tinib (a tyrosine kinase inhibitor that also binds to the HER2 receptor), pertuzum- ab (an anti-HER2 antibody) and T-DM1 (an antibody-drug conjugate in which the cytotoxic substance emtansin (DM1) is bound to trastuzumab). HER2 receptors are also expressed on cardiomyocytes (5). The generally accepted putative mecha- nism of action of anti-HER2 drugs are the changes in the structure and function of Ta bl e 1: G en er al fa ct or s t ha t m ak e pa tie nt s m or e su sc ep tib le to d ev el op in g ca rd io to xi ci ty (2 ,6 ). LV – le ft ve nt ric le , P CI – p er cu ta ne ou s a ng io pl as ty , C AB G – Co ro na ry a rt er y by pa ss g ra fti ng . De m og ra ph ic fa ct or s Li fe st yl e fa ct or s Cu rr en t c ar di ol og ic al st at e Pr ev io us ca rd io to xi c th er ap y Ag e (p ae di at ric p op ul at io n < 18 y ea rs , a ge o ve r 65 y ea rs w ith a nt hr ac yc lin e tr ea tm en t a nd a ge ov er 5 0 ye ar s w ith T ra st uz um ab th er ap y) . Sm ok in g. He ar t f ai lu re (r eg ar dl es s o f L V ej ec tio n fra ct io n) . Pr ev io us a nt hr ac yc lin e tr ea tm en ts . Fa m ily h ist or y of e ar ly ca rd io va sc ul ar d is ea se (o ns et b ef or e ag e 50 ). O be si ty . As ym pt om at ic LV d ys fu nc tio n. Pr ev io us m ed ia st in al o r c he st w al l i rr ad ia tio n. Ar te ria l h yp er te ns io n. Ex ce ss iv e al co ho l c on su m pt io n. El ev at ed se ru m b io m ar ke r v al ue s b ef or e th e st ar t o f o nc ol og ic al tr ea tm en t. Di ab et es . Pr ed om in an tly se de nt ar y lif es ty le w ith ou t s uff ic ie nt ph ys ic al a ct iv ity . Co ro na ry h ea rt d is ea se (p rio r m yo ca rd ia l in fa rc tio n, a ng in a pe ct or is , c on di tio n fo llo w in g PC I o r C AB G) . Hy pe rc ho le st er ol em ia . M od er at e or se ve re va lv e fa ilu re w ith hy pe rt ro ph y or im pa ire d LV fu nc tio n. Hy pe rt en si ve h ea rt d is ea se w ith LV hy pe rt ro ph y. Ca rd io m yo pa th ie s: • ca rd ia c s ar co id os is w ith m yo ca rd ia l in vo lv em en t, • si gn ifi ca nt ca rd ia c a rr hy th m ia s ( e. g. , a tr ia l fib ril la tio n, v en tr ic ul ar ta ch yc ar di as ). Diagnostic method Current diagnostic criteria Echocardiography (3D estimate of LV ejection fraction, 2D estimate of LV ejection fraction according to Simpson, GLS) LVEF: decrease of 10 % below the lower limit of normal signifies cardiotoxicity. GLS: a relative decrease of > 12 % from the basal measurement indicates the possibility of cardiotoxicity or an absolute decrease of 5 %. Nuclear cardiac imaging (MUGA-multigated radionuclide angiography) A reduction of 10% of the LV ejection fraction to a value below 50 % signifies cardiotoxicity. Magnetic resonance imaging of the heart It is mostly a supplementary method when other techniques are not conclusive, or to confirm LV dysfunction at borderline pathological LVEF. Serum biomarkers (troponin I, high-sensitivity troponin I, BNP, NT-proBNP) An increase in troponin might help identify patients for whom the addition of an ACE inhibitor would be beneficial during treatment with anthracyclines. Routine use of BNP and NT-proBNP in the monitoring of high- risk patients requires further research. Table 2: Diagnostic methods for the detection of heart failure (summarized after (2) and (6)). LP - left ventricle, GLS - global longitudinal strain, LVEF - left ventricular ejection fraction, BNP - B-type natriuretic peptide, NT-proBNP - N-terminal segment of B-type natriuretic peptide, ACE - angiotensin-converting enzyme. 436 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2020 | Volume 89 | https://doi.org/10.6016/ZdravVestn.2934 contractile proteins and mitochondria in the myocardium, which do not lead to cell death but to damage of the contractile el- ements of cardiomyocytes. This explains the reversibility of trastuzumab cardio- toxicity (2). Clinically, the cardiotoxicity of trastuzumab is mostly manifested as an acute decrease in left ventricular ejection fraction (LVEF) or as symptomatic heart failure, which usually resolves upon dis- continuation of treatment and initiation of supportive cardioprotective therapy (2). Trastuzumab treatment leads to heart failure syndrome in 1.7–4.1%, while as- ymptomatic left ventricular dysfunction is more common (7.1–18.6%) (12). In a 2012 Cochrane meta-analysis, the rela- tive risk of heart failure after trastuzumab treatment was 1.8% when analysing nearly 12,000 women with HER2-positive breast cancer (13). The incidence of cardiotoxic- ity may further increase in patients treat- ed concomitantly with anthracyclines (2,5,13). As concomitant use of anthra- cyclines and trastuzumab is not recom- mended, the drugs are used sequentially in the treatment of breast cancer (14). The cardiotoxicity of other anti-HER2 drugs is similar to that of trastuzumab (15-17). Vascular endothelial growth factor (VEGF) inhibitors are also a group of drugs that can cause type II myocardial damage, which can lead to heart failure. The mecha- nism of cardiotoxicity is complex, as these inhibit multiple signalling pathways in the cell simultaneously. The myocardium is af- fected by both anti-VEGF antibodies (bev- acizumab, ramucirumab) and tyrosine ki- nase inhibitors (2). In a meta-analysis of more than 10,000 patients, the risk of de- veloping heart failure was 2.69-fold higher compared to control groups in which the patients were not treated with VEGF in- hibitors. The meta-analysis included treat- ment with the following tyrosine kinase inhibitors: sunitinib, sorafenib, pazopanib, axitinib, vandetanib, cabozantinib, pona- tinib and regorafenib (18). The prognosis of the outcome and the dynamics of the effects of cardiotoxicity of VEGF inhibi- tors are difficult to assess, as these drugs are usually used in the metastatic setting. Therefore, most patients die before the late effects of treatment can develop (2). 2.3 Myocardial damage after radiation therapy The harmful effects of radiotherapy on the heart have been known for a long time (5). Heart failure after irradiation can manifest itself acutely as myocarditis, but more often occurs after a long period of time (several years, even decades (19)). Irradiation can cause endothelial, micro- vascular, and macrovascular injury, valve injuries and damage, and pericarditis. Heart failure after radiotherapy is caused by interstitial myocardial fibrosis (19), and the clinical manifestation is determined by the amount and distribution of the re- sulting fibrosis (19,20). Myocardial fibro- sis usually develops at an irradiation dose above 30 Gy (19). The presence of general risk factors for cardiovascular disease and possible treatment with cardiotoxic drugs further increase the likelihood of heart failure in patients who have also been irra- diated as a part of cancer treatment (2,5). Adverse effects of irradiation are most commonly seen in patients treated for ear- ly-stage breast cancer or in patients after treatment for lymphoma in the mediasti- num (19), in whom the heart cannot be completely removed from the irradiated field. It is important to know that heart failure can also occur decades after medi- astinal irradiation (21). 2.4 Newer drugs and immunotherapy Heart failure syndrome can occur af- ter ischemic heart disease that with vari- ous chemotherapeutic agents (fluoropy- rimidines, platinum derivatives) as well as during treatment with target drugs (VEGF inhibitors), after radiotherapy or after treatment with hormonal drugs, e.g., aromatase inhibitors used to treat breast 437 PROFESSIONAL ARTICLE Heart failure and oncologic treatment cancer patients for several years (2,22). Immunotherapy is currently hot topic in oncology, especially treatment with im- mune checkpoint inhibitors, which caus- es otherwise rare adverse effects on the heart, as they occur in less than 1 % (23)). Immune checkpoint inhibitors act by a mechanism boosting the immune sys- tem response, which then attacks cancer, and occasionally its own cells. So far, we have found descriptions in the literature of some cases of myocarditis (also of the fulminant course), which occurred as part of immunotherapy (24-26). The long-term effects of immunotherapy on the cardio- vascular system are not yet known, as the drugs in question are newer and long-term experience is yet to be obtained. 3 Possibilities of preventing heart failure in oncological patients 3.1 General screening For each patient treated with one of the possible cardiotoxic drugs, it is necessary to first determine the basic risk factors for the development of cardiotoxicity (Table 1) and try to influence those factors that can be regulated by non-pharmacological measures (promotion of a healthy lifestyle, regular aerobic exercise, smoking cessa- tion, and abstinence from alcoholic bever- ages) (2). Further screening methods are laboratory (determination of natriuretic peptides, determination of troponin I or T) and imaging (echocardiography, magnetic resonance imaging of the heart, nuclear cardiac imaging). The recommendations of the European Society of Cardiology leave the choice of modalities upon local expertise and availability (poorer avail- ability of magnetic resonance imaging nuclear cardiac imaging), while recom- mending the use of the same algorithm in individual patient monitoring (2). Sever- al different scoring predictive models of cardiotoxicity have also been published, but they have not yet been prospectively validated, so they are not widely used in everyday practice (2,5). The proposed di- agnostic methods are presented in Table 2. At the beginning of 2020, the recommen- dations of the European Society for Medi- cal Oncology (ESMO) for the monitoring and cardiac treatment of oncological pa- tients were also published (6). 3.1.1 Echocardiography Echocardiography is recommended as the main screening method. Whenever possible, 3D assessment of the left ven- tricular ejection fraction is recommended, but if 3D LVEF assessment is not possible, the guidelines still recommend 2D left ventricular ejection fraction estimation using the Simpson method (2,4,6). Car- diotoxicity is defined as a 10% decrease in the LVEF below the lower normal limit (4). If signs of cardiotoxicity are observed during treatment with cardiotoxic che- motherapeutics, ultrasound examination of the heart should be repeated after 2-3 weeks to confirm cardiotoxicity (4). Due to the interobserver variability of the method, it is recommended that the examination is performed by the same examiner whenever possible (4). The use of contrast echocardiography should be considered when visibility is poor. Stress echocardiography discover additional pa- tients with a high risk of developing car- diotoxicity, although the data is current- ly insufficient to support the routine use of this test in screening patients prior to the start of the oncological treatment (2). Measurements of myocardial deformity are highly recommended, as GLS (global longitudinal strain) assessment is used to determine impaired myocardial systol- ic function before the global parameters of myocardial systolic function decrease (LVEF is most commonly used) (27). Cardiotoxicity occurs when the GLS is re- duced by 12% or more from the baseline value, or when there is an absolute reduc- tion of 5 points or more (6). The GLS is expected to have better reproducibility, 438 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2020 | Volume 89 | https://doi.org/10.6016/ZdravVestn.2934 with smaller variability deviations than the classic LVEF measurements (6). Dia- stolic dysfunction is commonly identified in cancer patients both before and during treatment. To date, there is no evidence to support changes of oncological treatment plan solely on the basis of the presence of diastolic dysfunction (2). 3.1.1.2 Nuclear cardiac imaging and magnetic resonance imaging (MRI) Nuclear cardiac imaging is a well-re- producible method, but it exposes the pa- tient to irradiation and provides much less information about the morphology and structure of the heart than echocardiogra- phy (5). A heart MRI is an accurate im- aging method that provides a lot of infor- mation about the structure and function of the myocardium and is most often used as a complementary method to clarify the cause of left ventricular dysfunction (28). It is also useful for assessing the pericar- dium, especially in patients who have had chest irradiation. The use of Gadolinium contrast medium allows for the most ac- curate assessment of myocardial fibrosis of all other imaging modalities (2,28). However, due to the procedure of image capture and mostly qualitative analysis, diffuse myocardial fibrosis can be missed after treatment with anthracyclines (28). 3.1.1.3 Determination of serum biomarkers of myocardial damage and heart failure Determination of serum biomarkers of myocardial damage and heart failure probably makes sense in early detection of cardiotoxicity, but based solely on elevat- ed values without other evidence; without other evidence of myocardial dysfunc- tion, discontinuation or modification of oncological treatment should not be con- sidered (2,6). Further research is neces- sary to determine the optimal timeframe for the identification of these biomarkers and their reference values, that would guide further actions and predict patient outcome (2,5,6). Individual recommen- dations for the determination of serum markers according to the used method of treatment are presented below. The ESC recommendations conclude that the choice of methods and frequency of cardiotoxicity monitoring during/after oncological treatment should be tailored to each patient as well as the accessibility and capabilities in the treatment environ- ment (2). 3.2 Screening according to the type of oncological treatment 3.2.1 Anthracyclines A baseline assessment of cardiac func- tion is recommended for all patients re- ceiving treatment with anthracyclines (2,4,6,29). If systolic function is reduced (LVEF below 40%) or if significant valve pathology is present, consultation with a cardiologist or consideration of changing the therapeutic regimen (discontinuation of anthracyclines, replacement with anoth- er, non-cardiotoxic drug) is required (29). For treatment with higher doses of anthra- cyclines, cardiac function (echocardiogra- phy, including 3D assessment of LVEF and GLS) should be re-evaluated (4) as soon as a cumulative dose of doxorubicin 250 mg/m2 or an equivalent dose of a differ- ent anthracycline is reached, and then be- fore each additional 50 mg/m2 increment (2,4,6,30). Ultrasound monitoring is also recommended 12 and 18 months from the start of anthracycline treatment, regardless of the cumulative dose received (6,29,30). Following the completion of anthracycline therapy, the new ESMO recommendations state that a patient should be monitored by ultrasound at 6–12 months and for 2 years after completion of treatment if there are no symptoms (6). In patients receiving anthracyclines, it is also recommended to perform a base- line determination of serum biomarkers for heart muscle damage and heart failure – the high-sensitivity troponin I or T and natriuretic peptides (2,6). Measurements of troponin and natriuretic peptides levels 439 PROFESSIONAL ARTICLE Heart failure and oncologic treatment can be repeated with each anthracycline cycle (6). An early increase in troponin I value during anthracycline treatment is in 34% connected with the development of diastolic dysfunction (31). Troponin is useful in this population especially due to its high negative predictive value. This means that patients who do not have an increased troponin values during treat- ment have only a minimum risk of devel- oping early cardiotoxicity (32). However, it has not yet been demonstrated that de- termining troponin values a regular basis prevents or reduces the number of cardiac events due to late cardiotoxicity after an- thracycline treatment (2). The ESC recom- mendations conclude that an increase in any of the serum biomarkers of heart mus- cle damage and heart failure may identify patients who are more prone to developing heart failure and are likely to need more careful monitoring (2). The new ESMO recommendations advise the introduction of cardioprotective treatment based on the observed increase in troponin (6). In study of Cardinal et collegues, an analysis of over 2,500 patients showed that most cases of anthracycline cardiotoxicity were asymptomatic left ventricular dys- function that occurred within the first year after treatment (9). This underlines the need of regular screening of all patients af- ter completion of anthracycline treatment. The same working group also found that with anthracycline cardiotoxicity, early introduction of heart failure therapy (in their case, enalapril and carvedilol) leads to a significantly more effective treatment of heart failure, which further supports regular ultrasound monitoring of anthra- cycline-treated patients (11). 3.2.2 Trastuzumab Analogous to antracyclin treatment, baseline ultrasound assessment of cardi- ac function is recommended prior tras- tuzumab therapy. During treatment with trastuzumab, in asymptomatic patients, ultrasound assessment of cardiac func- tion is recommended for every 3 months of treatment (2,4,6,29). If the ultrasound result is normal, ultrasound monitoring is recommended for another 6–12 months and 2 years after the end of treatment (4,6) or for another 12 and 18 months from the start of treatment (29,30). Troponin level Table 3: Summary of patient monitoring recommendations (2,4,6,24,25). 1 – in the treatment of metastatic disease, a baseline assessment is recommended and then further assessments according to the course of the disease and the clinical picture. * – if possible, a 3D assessment is recommended; if not, 2D. ** – monitoring may also be performed by isotope ventriculography, but echocardiography is recommended. *** – the criterion previously met is taken into account. VEGF – vascular endothelial growth factor, GLS – global longitudinal strain. Method of treatment Recommendations Anthracycline treatments1 Baseline assessment by echocardiography, including 3D* assessment of LVEF, GLS and troponin I (or nuclear cardiac imaging**). GLS echocardiography at achieved cumulative doxorubicin dose at 250 mg/m2, followed by additional 50 mg/m2 increments. Echocardiography 6–12 months and 2 years from the start of treatment. Trastuzumab treatment1 Baseline assessment by echocardiography, including 3D* assessment of LVEF, GLS and troponin I Echocardiography every 3 months of treatment, including GLS and determination of troponin I. Echocardiography for another 12 and 18 months from the start of treatment. VEGF inhibitor treatment Baseline assessment by echocardiography. In high-risk patients, reassessment after 2–4 weeks of treatment. Echocardiography every 6 months. Radiotherapy treatment If the patient has also been treated with other cardiotoxic substances, see recommendations: start of screening 5 years after the end of treatment or after 30 years of age*** 440 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2020 | Volume 89 | https://doi.org/10.6016/ZdravVestn.2934 determination on a regular basis is also recommended in patients with high risk for onset of cardiotoxicity (2). Elevated troponin levels have been associated with the development of acute cardiotoxicity and the development of persistent myo- cardial damage during adjuvant therapy with trastuzumab (33). In a study by Saway et al., the high-sensitivity troponin I and GLS, determined after anthracycline treat- ment and before the start of trastuzumab treatment, were shown to be predictors of trastuzumab-related cardiotoxicity with 93% sensitivity and 91% negative predic- tive value (34). 3.2.3 VEGF inhibitors The exact time frame for monitoring cardiac function in VEGF inhibitor ther- apy has not yet been established. In any case, it is recommended to assess cardiac function at baseline and then reassess the condition in high-risk patients 2–4 weeks after starting treatment with sunitinib, sorafenib and pazopanib and to monitor their condition every 6 months (2). Con- tinuous blood pressure measurements (arterial hypertension is one of the most common side effects of this treatment) and adjustments of antihypertensive ther- apy in the light of the management of the patient’s cardiovascular risk factors are al- so recommended (6). 3.2.4 Radiotherapy The main options for preventing myo- cardial damage in radiotherapy treatment are improved irradiation techniques that are more accurate and more fractionat- ed with lower doses and less damage to surrounding tissue (19). After radiother- apy, screening recommendations differ. In most cases, it is recommended to start screening 5 years after the end of treat- ment or after the age of 30, depends which criteria is met earlier (19). Thereafter, monitoring is continued every 3–5 years (6). However, these are often patients who have been treated with anthracyclines or trastuzumab at the same time, so in this case, we follow the guidelines that apply to follow-up with these drugs. Screening methods without excessive irradiation (for example ultrasound) and are non-invasive are recommended in the first place (19). 3.2.5 Immunotherapy Recommendations for follow-up of pa- tients treated with immunotherapy (par- ticularly immune checkpoint inhibitors) are based on expert consensus with data from retrospective analyses or observa- tional prospective studies. If a patient de- velops symptoms of cardiotoxicity during treatment, a cardiologist should be con- sulted immediately, serum biomarkers need to be determined, and echocardiog- raphy or magnetic resonance imaging of the heart performed searching for miocar- ditis. Regular screening of asymptomatic patients or long-term cardiac monitoring of patients is not required. Only monitor- ing of patients with observed cardiotoxici- ty further is advised (6). The recommendations for the cardi- ac follow-up of patients during and after oncological treatment are summarized in Table 3. 4 Prevention and treatment of heart failure caused by oncological treatment 4.1 Prevention of heart failure in oncological patients Prophylactic use of cardioprotective drugs (ACE inhibitors, sartans, beta block- ers and mineralocorticoid antagonists) in all patients is not yet widely accepted due to inconsistent data in the literature re- garding the effectiveness of this approach. Cochran’s meta-analysis (13), which in- cluded randomized trials of cardioprotec- tive drugs in cancer patients published so far, showed that none of the drugs tested had statistically significant cardiac protec- tion. In two smaller studies of 50 patients, carvedilol (35) and nebivolol (36) were 441 PROFESSIONAL ARTICLE Heart failure and oncologic treatment shown to be effective in preventing LVEF lowering, and in a retrospective analysis of 315 patients, patients taking beta-block- ers during oncology treatment had lower incidence of heart failure with both anth- racyclines and trastuzumab (37). A pro- spective, randomized OVERCOME study demonstrated a lower incidence of heart failure and LVEF reduction in the preven- tive use of the combination of enalapril and carvedilol in patients treated with an- thracyclines (38). Two studies on positive effects on sartan valsartan (39) and telmis- artan (40) have also been published. They have shown that sartans (valsartan) can successfully prevent a transient increase in LV end-diastolic diameter and chang- es in the QTc interval in the ECG (39) and telmisartan can prevent a decrease in GLS (40). A study of 83 breast cancer pa- tients, treated with anthracyclines, further showed that prophylactic use of spirono- lactone successfully prevented the devel- opment of both systolic and diastolic myo- cardial dysfunction (41). In patients who tested positive for troponin during anth- racycline treatment, taking an ACE inhib- itor has been shown to significantly reduce LVEF decline and the likelihood of heart failure (42). However, an observational retrospective analysis of approximately 200 breast cancer patients receiving anth- racyclines showed that patients were less likely to be hospitalized for symptomatic heart failure if they received statins con- tinuously than those who did not receive statins or did not take them continuously (43). Prospective randomized research on the cardioprotective role of statins is cur- rently underway. Based on these data, ESC recommen- dations advise consideration on initiat- ing cardioprotective treatment in patients with a positive troponin I value (2). How- ever, the ESMO guidelines advise the introduction of cardioprotective drugs (ACE inhibitors, sartans and beta-block- ers) before starting treatment in patients with known risk factors for cardiotoxicity when they are to be treated with cardio- toxic drugs (6). Dexrazoxane is recom- mended as a cardioprotective drug only in the treatment of metastatic breast cancer if the 300 mg/m2 maximum cumulative dose of doxorubicin has already been reached (6,29). The ESMO guidelines recommend the introduction of cardioprotective drugs even in asymptomatic patients with an- thracyclines who have a fall in LVEF of more than 10% from baseline to 50%, or a reduction in LVEF of 40-50%. They al- so recommend the introduction of drugs in asymptomatic patients treated with trastuzumab and a fall in LVEF of more than 10% from baseline or a reduction in LVEF of 40-50%. A new development in ESMO recommendations compared to the ESC guidelines is the recommendation to introduce cardioprotective therapy in as- ymptomatic patients with normal LVEF, regardless of the type of cardiotoxic drugs and a reduction in GLS (absolute reduc- tion of 5% or more, or relative reduction of 12% or more). ESMO recommendations also recommend the introduction of car- dioprotective therapy in patients treated with anthracyclines who develop elevated troponin levels during treatment (with the simultaneous exclusion of ischemic heart disease) (6). There are currently no studies or rec- ommendations on cardioprotective treat- ment with immunotherapy. 4.2 Treatment of heart failure in oncological patients If a cancer patient develops heart fail- ure syndrome, a timely definitive diagno- sis of the causes of heart failure and the introduction of cardioprotective drugs ac- cording to current ESC recommendations are required (44). In cancer patients, the classic causes of heart failure (ischemic heart disease, val- vular disease, heart failure due to hyper- tension and cardiomyopathy) should also be considered when diagnosing the aeti- ology of heart failure. In some cases (e.g., 442 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2020 | Volume 89 | https://doi.org/10.6016/ZdravVestn.2934 by myocardial revascularization, valve repair/replacement, regulation of blood pressure), we can significantly influence the course and outcome of treatment of heart failure (44). Toxic cardiomyopathy associated with oncological treatment is usually a diagnosis made when all other, more common causes of heart failure have been ruled out. The definitive diagnosis of toxic cardiomyopathy is otherwise histo- logical. However, in practice, myocardial biopsy is performed only in cases when non-invasive tests cannot prove the diag- nosis reliably enough, or when histologi- cal examination could significantly change further oncological treatment or treat- ment of heart failure. Regardless of the aetiology of heart failure, cardioprotective drugs should be introduced as soon as the patient is diag- nosed with heart failure (clinical manifes- tation, elevated natriuretic peptides, signs of heart failure on echocardiography). There is growing evidence that early intro- duction is associated with greater success in the treatment of toxic cardiomyopathy (45). Patients with toxic cardiomyopa- thy resulting from oncological treatment have the same principles of treatment for heart failure as the general population. In patients who develop a heart failure phe- notype with reduced left ventricular ejec- tion fraction (LVEF < 40 %; i.e., HFrEF); treatment is based on a combination of renin-angiotensin-aldosterone axis inhi- bition (with ACE inhibitors, sartans, be- ta-blockers and mineralocorticoid antago- nists) and neurohumoral modulation with neprilysin inhibitors (which replace ACE inhibitors or sartans). The prognostic role of this treatment in patients with a heart failure phenotype with preserved ejection fraction (LVEF > 50 %; i.e., HFpEF) is less clear. To date, there has been no clear evi- dence to support the use of cardioprotec- tive drugs in this patient population. Re- gardless of the phenotype of heart failure in symptomatic patients with heart failure, we also use symptomatic drugs (diuretics, nitrates, digoxin), which effectively reduce the symptoms and signs of heart failure, but do not affect the outcome of the dis- ease. The duration of treatment for heart failure in oncological patients is not clear- ly defined. Depending on the type and the duration of treatment, we decide accord- ing to the patient’s initial laboratory and imaging results, according to their trends of improvement or deterioration, and ac- cording to the patient’s well-being. With complete restitution of cardiac function, a reduction or even discontinuation of cardioprotective drugs (the latter is rarely chosen) can be considered with persistent normal laboratory and imaging results. In the event of a worsening heart failure despite optimal drug treatment, other measures (e.g., a pacemaker) may be con- sidered in this patient population as well. However, levosimendan infusion should be applied patients with advanced heart failure (44). An active malignant disease or a malignant disease in the last 5 years is the absolute contraindication for perform- ing a heart transplantation or a mechani- cal support of blood circulation, which is why oncological patients are generally not suitable for this type of treatment. Howev- er, if more than 5 years have passed since the end of treatment and the patients are in stable remission, heart transplants or mechanical circulatory support are also possible for these patients. The final opin- ion on this in our country is always given by the Council for Transplantation of the Advanced Heart Failure and Transplanta- tion Program. 5 Conclusion Heart failure is an important conse- quence of oncological treatment. Timely diagnosis, early treatment and referral to skilled cardiologic center can significant- ly improve the outcome in patients who develop heart failure after otherwise suc- cessful oncological treatment. Due to the growing number of cardio-oncological patients, they are establishing focused car- 443 PROFESSIONAL ARTICLE Heart failure and oncologic treatment dio-oncology centres around the world that provide a more standardized treat- ment of these patients. We do not have such a treatment model yet. Such timely References 1. Rak v Sloveniji 2015. Ljubljana: Onkološki inštitut Ljubljana, Epidemiologija in register raka, Register raka Republike Slovenije; 2016. 2. Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, et al.; ESC Scientific Document Group. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(36):2768-801. DOI: 10.1093/eurheartj/ehw211 PMID: 27567406 3. Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: time to recognize a new entity. J Clin Oncol. 2005;23(13):2900-2. DOI: 10.1200/JCO.2005.05.827 PMID: 15860848 4. Plana JC, Galderisi M, Barac A, Ewer MS, Ky B, Scherrer-Crosbie M, et al. Expert consensus for multimodality imaging evaluation of adult patients during and after cancer therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2014;27(9):911-39. DOI: 10.1016/j.echo.2014.07.012 PMID: 25172399 5. Bloom MW, Hamo CE, Cardinale D, Ky B, Nohria A, Baer L, et al. Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 1: Definitions, Pathophysiology, Risk Factors, and Imaging. Circ Heart Fail. 2016;9(1):e002661. DOI: 10.1161/CIRCHEARTFAILURE.115.002661 PMID: 26747861 6. Curigliano G, Lenihan D, Fradley M, Ganatra S, Barac A, Blaes A, et al.; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol. 2020;31(2):171-90. DOI: 10.1016/j.annonc.2019.10.023 PMID: 31959335 7. Lyu YL, Kerrigan JE, Lin CP, Azarova AM, Tsai YC, Ban Y, et al. Topoisomerase IIbeta mediated DNA double- strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res. 2007;67(18):8839-46. DOI: 10.1158/0008-5472.CAN-07-1649 PMID: 17875725 8. Blanco JG, Sun CL, Landier W, Chen L, Esparza-Duran D, Leisenring W, et al. Anthracycline-related cardiomyopathy after childhood cancer: role of polymorphisms in carbonyl reductase genes—a report from the Children’s Oncology Group. J Clin Oncol. 2012;30(13):1415-21. DOI: 10.1200/JCO.2011.34.8987 PMID: 22124095 9. Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131(22):1981-8. DOI: 10.1161/ CIRCULATIONAHA.114.013777 PMID: 25948538 10. Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA. 1991;266(12):1672-7. DOI: 10.1001/jama.1991.03470120074036 PMID: 1886191 11. Cardinale D, Colombo A, Lamantia G, Colombo N, Civelli M, De Giacomi G, et al. Anthracycline-induced cardiomyopathy: clinical relevance and response to pharmacologic therapy. J Am Coll Cardiol. 2010;55(3):213-20. DOI: 10.1016/j.jacc.2009.03.095 PMID: 20117401 12. Bowles EJ, Wellman R, Feigelson HS, Onitilo AA, Freedman AN, Delate T, et al.; Pharmacovigilance Study Team. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst. 2012;104(17):1293-305. DOI: 10.1093/jnci/djs317 PMID: 22949432 13. Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;4(4):CD006243. DOI: 10.1002/14651858.CD006243. pub2 PMID: 22513938 14. Žgajnar J. Smernice diagnostike in zdravljenja raka dojk. Ljubljana: Onkološki inštitut Ljubljana; 2014. 15. Lenihan D, Suter T, Brammer M, Neate C, Ross G, Baselga J. Pooled analysis of cardiac safety in patients with cancer treated with pertuzumab. Ann Oncol. 2012;23(3):791-800. DOI: 10.1093/annonc/mdr294 PMID: 21665955 and high-quality treatment of cardiac-on- cological patients is ensured through good cooperation between the oncologist, gen- eral practitioner and cardiologist. 444 CARDIOVASCULAR SYSTEM Zdrav Vestn | July – August 2020 | Volume 89 | https://doi.org/10.6016/ZdravVestn.2934 16. Krop IE, Suter TM, Dang CT, Dirix L, Romieu G, Zamagni C, et al. Feasibility and cardiac safety of trastuzumab emtansine after anthracycline-based chemotherapy as (neo)adjuvant therapy for human epidermal growth factor receptor 2-positive early-stage breast cancer. J Clin Oncol. 2015;33(10):1136-42. DOI: 10.1200/JCO.2014.58.7782 PMID: 25713436 17. Piccart-Gebhart M, Holmes E, Baselga J, de Azambuja E, Dueck AC, Viale G, et al. Adjuvant lapatinib and trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: results from the randomized phase III Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial. J Clin Oncol. 2016;34(10):1034-42. DOI: 10.1200/JCO.2015.62.1797 PMID: 26598744 18. Ghatalia P, Morgan CJ, Je Y, Nguyen PL, Trinh QD, Choueiri TK, et al. Congestive heart failure with vascular endothelial growth factor receptor tyrosine kinase inhibitors. Crit Rev Oncol Hematol. 2015;94(2):228-37. DOI: 10.1016/j.critrevonc.2014.12.008 PMID: 25577572 19. Jaworski C, Mariani JA, Wheeler G, Kaye DM. Cardiac complications of thoracic irradiation. J Am Coll Cardiol. 2013;61(23):2319-28. DOI: 10.1016/j.jacc.2013.01.090 PMID: 23583253 20. Filopei J, Frishman W. Radiation-induced heart disease. Cardiol Rev. 2012;20(4):184-8. DOI: 10.1097/ CRD.0b013e3182431c23 PMID: 22314140 21. van Nimwegen FA, Schaapveld M, Janus CP, Krol AD, Petersen EJ, Raemaekers JM, et al. Cardiovascular disease after Hodgkin lymphoma treatment: 40-year disease risk. JAMA Intern Med. 2015;175(6):1007-17. DOI: 10.1001/jamainternmed.2015.1180 PMID: 25915855 22. Matthews A, Stanway S, Farmer RE, Strongman H, Thomas S, Lyon AR, et al. Long term adjuvant endocrine therapy and risk of cardiovascular disease in female breast cancer survivors: systematic review. BMJ. 2018;363:k3845. DOI: 10.1136/bmj.k3845 PMID: 30297439 23. Haanen J, Carbonnel F, Robert C, Kerr K, Peters S, Larkin J, et al. Management of Toxicities from Immunotherapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2017;28(4):iv119-42. DOI: 10.1093/annonc/ mdx225 24. Johnson DB, Balko JM, Compton ML, Chalkias S, Gorham J, Xu Y, et al. Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med. 2016;375(18):1749-55. DOI: 10.1056/ NEJMoa1609214 PMID: 27806233 25. Tadokoro T, Keshino E, Makiyama A, Sasaguri T, Ohshima K, Katano H, et al. Acute lymphocytic myocarditis with anti-PD-1 antibody nivolumab. Circ Heart Fail. 2016;9(10):e003514. DOI: 10.1161/ CIRCHEARTFAILURE.116.003514 PMID: 27650418 26. Läubli H, Balmelli C, Bossard M, Pfister O, Glatz K, Zippelius A. Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J Immunother Cancer. 2015;3(1):11. DOI: 10.1186/s40425-015-0057-1 PMID: 25901283 27. Negishi K, Negishi T, Hare JL, Haluska BA, Plana JC, Marwick TH. Independent and incremental value of deformation indices for prediction of trastuzumab-induced cardiotoxicity. J Am Soc Echocardiogr. 2013;26(5):493-8. DOI: 10.1016/j.echo.2013.02.008 PMID: 23562088 28. Thavendiranathan P, Wintersperger BJ, Flamm SD, Marwick TH. Cardiac MRI in the assessment of cardiac injury and toxicity from cancer chemotherapy: a systematic review. Circ Cardiovasc Imaging. 2013;6(6):1080-91. DOI: 10.1161/CIRCIMAGING.113.000899 PMID: 24254478 29. Curigliano G, Cardinale D, Suter T, Plataniotis G, de Azambuja E, Sandri MT, et al.; ESMO Guidelines Working Group. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol. 2012;23(7):vii155-66. DOI: 10.1093/annonc/mds293 PMID: 22997448 30. Hamo CE, Bloom MW, Cardinale D, Ky B, Nohria A, Baer L, et al. Cancer Therapy-Related Cardiac Dysfunction and Heart Failure: Part 2: Prevention, Treatment, Guidelines, and Future Directions. Circ Heart Fail. 2016;9(2):e002843. DOI: 10.1161/CIRCHEARTFAILURE.115.002843 PMID: 26839395 31. Cardinale D, Bacchiani G, Beggiato M, Colombo A, Cipolla CM. Strategies to prevent and treat cardiovascular risk in cancer patients. Semin Oncol. 2013;40(2):186-98. DOI: 10.1053/j. seminoncol.2013.01.008 PMID: 23540744 32. Cardinale D, Sandri MT, Colombo A, Colombo N, Boeri M, Lamantia G, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004;109(22):2749-54. DOI: 10.1161/01.CIR.0000130926.51766.CC PMID: 15148277 33. Cardinale D, Colombo A, Torrisi R, Sandri MT, Civelli M, Salvatici M, et al. Trastuzumab-induced cardiotoxicity: clinical and prognostic implications of troponin I evaluation. J Clin Oncol. 2010;28(25):3910- 6. DOI: 10.1200/JCO.2009.27.3615 PMID: 20679614 34. Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Tan TC, et al. Assessment of echocardiography and biomarkers for the extended prediction of cardiotoxicity in patients treated with anthracyclines, taxanes, and trastuzumab. Circ Cardiovasc Imaging. 2012;5(5):596-603. DOI: 10.1161/CIRCIMAGING.112.973321 PMID: 22744937 445 PROFESSIONAL ARTICLE Heart failure and oncologic treatment 35. Kalay N, Basar E, Ozdogru I, Er O, Cetinkaya Y, Dogan A, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol. 2006;48(11):2258-62. DOI: 10.1016/j. jacc.2006.07.052 PMID: 17161256 36. Kaya MG, Ozkan M, Gunebakmaz O, Akkaya H, Kaya EG, Akpek M, et al. Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study. Int J Cardiol. 2013;167(5):2306-10. DOI: 10.1016/j.ijcard.2012.06.023 PMID: 22727976 37. Seicean S, Seicean A, Alan N, Plana JC, Budd GT, Marwick TH. Cardioprotective effect of β-adrenoceptor blockade in patients with breast cancer undergoing chemotherapy: follow-up study of heart failure. Circ Heart Fail. 2013;6(3):420-6. DOI: 10.1161/CIRCHEARTFAILURE.112.000055 PMID: 23425978 38. Bosch X, Rovira M, Sitges M, Domènech A, Ortiz-Pérez JT, de Caralt TM, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies). J Am Coll Cardiol. 2013;61(23):2355-62. DOI: 10.1016/j.jacc.2013.02.072 PMID: 23583763 39. Nakamae H, Tsumura K, Terada Y, Nakane T, Nakamae M, Ohta K, et al. Notable effects of angiotensin II receptor blocker, valsartan, on acute cardiotoxic changes after standard chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone. Cancer. 2005;104(11):2492-8. DOI: 10.1002/ cncr.21478 PMID: 16247790 40. Cadeddu C, Piras A, Mantovani G, Deidda M, Dessì M, Madeddu C, et al. Protective effects of the angiotensin II receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress, and early ventricular impairment. Am Heart J. 2010;160(3):487.e1-7. DOI: 10.1016/j.ahj.2010.05.037 PMID: 20826257 41. Akpek M, Ozdogru I, Sahin O, Inanc M, Dogan A, Yazici C, et al. Protective effects of spironolactone against anthracycline-induced cardiomyopathy. Eur J Heart Fail. 2015;17(1):81-9. DOI: 10.1002/ejhf.196 PMID: 25410653 42. Cardinale D, Colombo A, Sandri MT, Lamantia G, Colombo N, Civelli M, et al. Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition. Circulation. 2006;114(23):2474-81. DOI: 10.1161/CIRCULATIONAHA.106.635144 PMID: 17101852 43. Seicean S, Seicean A, Plana JC, Budd GT, Marwick TH. Effect of statin therapy on the risk for incident heart failure in patients with breast cancer receiving anthracycline chemotherapy: an observational clinical cohort study. J Am Coll Cardiol. 2012;60(23):2384-90. DOI: 10.1016/j.jacc.2012.07.067 PMID: 23141499 44. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al.; ESC Scientific Document Group. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37(27):2129-200. DOI: 10.1093/eurheartj/ehw128 PMID: 27206819 45. Fadol AP. Management of Chemotherapy-Induced Left Ventricular Dysfunction and Heart Failure in Patients With Cancer While Undergoing Cancer Treatment: the MD Anderson Practice. Front Cardiovasc Med. 2018;5:24. DOI: 10.3389/fcvm.2018.00024 PMID: 29644219