Submit Your Article CMED MEACR meeting
Home Print this page Email this page Users Online: 272
Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
Year : 2017  |  Volume : 6  |  Issue : 5  |  Page : 207-213

Mechanisms and biomarkers to detect chemotherapy-induced cardiotoxicity

1 Department of Cardiology, Atherosclerosis Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2 Department of Biochemistry, Hyperlipidemia Research Center, Diabetes Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
3 Department of Genetic, Clinical Research Development Unit, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
4 Department of Biology, Laboratory of Stem Cells, DSST, Faculty of Sciences, Lebanese University, Beirut, Iran

Date of Web Publication30-Nov-2017

Correspondence Address:
Zeinab Deris Zayeri
Golestan Hospital Clinical Research Development Unit, Ahvaz Jundishapur University of Medical Sciences, Ahvaz
Login to access the Email id

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ccij.ccij_47_17

Rights and Permissions

A cardiotoxicity is a considerable event for cardiologists and oncologists during and after chemotherapy. The use of certain chemotherapy agents such as trastuzumab, programmed death-1 inhibitors, and Doxorubicin increased in cancer therapy; however, these agents associate with an increase in mortality and cardiotoxicity. Detecting cardiotoxicity is based on patient's medical history and physical examination since there is no exact biomarker or polymorphism for its early diagnosis. Therefore, we still need potential biomarkers for cardiotoxicity risk. Treatment of several cancers is manageable while preventing cardiotoxicity, as chemotherapy side effect, is essential since it might be a greater risk than the malignancy if not detected at early stages. Early detection of cardiotoxicity, during and after chemotherapy, is crucial to decrease permanent and devastating cardiac damages. Recently, troponin but also atrial-type and brain-type natriuretic peptides were reported as good diagnostic biomarkers for cardiotoxicity. Micro-RNAs and inflammatory mediators are candidates as prognostic biomarkers. Genetic biomarkers such as C282Y allele of hemochromatosis gene makes the patients more susceptible to cardiotoxicity; therefore, genome studies are valuable in predicting chemotherapy results. In this review, we present the mechanisms of developing chemotherapy-induced cardiotoxicity and biomarkers for its detection in patients. Echocardiographic techniques are very strong techniques which could be used along with biomarkers for more reliable and quicker diagnosis.

Keywords: Biomarkers, cancer, cardiotoxicity, chemotherapy, reactive oxygen species

How to cite this article:
Haybar H, Jalali MT, Zibara K, Zayeri ZD. Mechanisms and biomarkers to detect chemotherapy-induced cardiotoxicity. Clin Cancer Investig J 2017;6:207-13

How to cite this URL:
Haybar H, Jalali MT, Zibara K, Zayeri ZD. Mechanisms and biomarkers to detect chemotherapy-induced cardiotoxicity. Clin Cancer Investig J [serial online] 2017 [cited 2022 Jan 27];6:207-13. Available from:

  Introduction Top

Cancer treatment may affect bone marrow niche. In addition, there is a lack of specific clinical markers to predict cancer progression,[1] or chemotherapy-induced cardiotoxicity, as a side effect of chemotherapeutic agents. Cardiotoxicity may happen at the same period of chemotherapy, or years later, and can be divided into five categories: Cardiac systolic dysfunction, ischemia, arrhythmias, pericardial disease, and thrombophilia.[2],[3] According to the reversibility of myocardial damages, anticancer drugs which induce cardiotoxicity are classified into two groups. The first type of drugs, such as anthracyclines and alkylating agents, may cause direct cell death and irreversible damage to cardiomyocytes. However, the second type of anti-cancer drugs, such as trastuzumab, vascular endothelial growth factor inhibitors, and tyrosine kinase inhibitors,[3],[4] can modify normal cellular function by affecting the mitochondrial system and decreasing protein synthesis. Fortunately, the cardiotoxicity of this second type of chemotherapy agents is reversible when the drug is discontinued.

Several chemotherapy agents such as cytostatic antibiotics of the anthracycline class, alkylating agents including cyclophosphamide, busulfan, fluorouracil(FU) and programmed death-1 inhibitors can increase the sensitivity of malignant cells to chemotherapy and hence increase patients' survival.[5] These agents are new in cancer therapy and can induce, with a synergistic effect, cardiac events such as thrombosis, arrhythmias, and cardio myopathy.[6] Cardiotoxicity may associate with cardiac cell injury or reversible cardiac dysfunction.[7] Chemotherapy can increase thrombosis through endothelial injuries by changing adhesion protein's function and by activating the coagulation cascade.[8] Chemotherapy drugs such as alkylating agents can cause platelets aggregation through increasing thromboxane and activating arachidonic acid pathway.[8] Several chemotherapy agents such as doxorubicin can cause cell apoptosis and mitochondrial damage in cardiomyocytes through activating P53.[7] Patients who receive chemotherapy are at risk of cardiotoxicity during and even after the treatment, so monitoring cardiac events is a sensitive process in cancer patients. Detecting susceptible patients depend on symptoms but several patients are asymptomatic. In general, continuous cardiac monitoring, echocardiographic and radionuclide angiographies and cardiac biomarkers measurement are helpful in detecting susceptible patients who receive chemotherapy.[9],[10] Cardiotoxicity associated with different factors such as the type of the drug, dose administration, schedule of administration,[11] drug combination, and other factors.[12] The main problem in detecting cardiotoxicity is that it is based on functional impairments which prevents cardiotoxicity management in early stages.[13] Finding biomarkers and single nucleotide polymorphisms(SNPs) to diagnose and manage cardiotoxicity in early stages is important. High-dose chemotherapy increases cardiotoxicity in cancer patients and studies showed an increase in troponin serum levels which can be a good prognostic biomarker.[14] Indeed, troponin is a sensitive biomarker for detecting small necrosis in early stages. Troponin I and natriuretic peptides can be good diagnostic biomarkers in chemotherapy-induced cardiotoxicity.[13] Genome-wide association studies(GWAS) investigated several SNPs linked to early induced cardiotoxicity.[15] SNPs of genes such as ABBC1 and ABBC2, which encode adenosine triphosphate(ATP) binding cassette transporter, CYP3A4, CYP3A5, and CYP2C8 might also be associated to cardiotoxicity.[16] In this review, we discuss the pathways that induce cardiotoxicity in chemotherapy patients and we suggest several biomarkers for cardiotoxicity detection. We also discussed several SNPs and biomarkers that might be useful in diagnosing cardiotoxicity in early stages.

  Why Cardiac Issue Appears in Chemotherapy Patient Top


Cancer patients have an increased risk of thrombosis events.[17] In addition, chemotherapy agents are suspected to correlate with the high risk of venous thrombotic events(VTT) in cancer patients whose main cause is not clear yet.[18] Chemotherapy can be a risk factor in VTT development.[19] Several hereditary risk factors for VTT are detected such as factor V Leiden mutation.[17] Mutations in F5 gene that generate rs6025 and rs4524 polymorphisms which code for factor V Leiden mutations R506Q and K858R, respectively, associate with VTT in cancer patients.[20] Initially, cancer treatments affect the vascular system and cause hypertension, vasospasm, and thrombosis development whereas long-term toxicities develop at later stages such as atherosclerosis.[21] Multiple biomarkers including tissue factor, D-dimer, and soluble P-selectin are useful in detecting thrombosis while a single biomarker is not predictive in cancer patients.[22]

  Chemotherapy-Induced Cardiotoxicity Mechanisms Top

Increase in reactive oxygen species level

Reactive oxygen species(ROS) signaling pathways are increased in cardiovascular diseases and conditions such as atherosclerosis, cardiomyopathy, and heart failure(HF) development. ROS can oxidize cysteine residues on Ras directly and activate downstream signals to PI3K, Raf, mitogen-activated protein kinase and extracellular signal-regulated kinase(MAPK/ERK), and(ERK1/2).[23] PI3K/AKT/mTOR pathway activity increases in several types of cancer and its targeting can have proapoptotic and antiproliferative effects on cancers.[24]

Mitogen-activated protein kinase(MAPK) plays an important role in the regulation of myocardial apoptosis.[25] Chemotherapy agents such as anthracycline can generate ROS, activate Caspase 9, and finally, induce apoptosis in myocytes.[26] Increase in ROS levels leads to membrane damage and lipid peroxidation.[27] On the other hand, ROS decreases sarcoplasmic reticulum Ca +2_ATPase expression, enhances Ca +2 release, and finally, Ca +2 overload leads to myocardial necrosis.[28] Doxorubicin is a drug derived from a fungus [29] and is widely used to treat several types of tumors such as leukemia, lymphoma, and solid tumors.[30] Doxorubicin is harmful to the heart because it affects mitochondria through inducing ROS production and decreasing energy production so the heart as a pump will not work properly. Another possible mechanism for this drug is that ROS may stimulate c-Jun N-terminal kinase(JNK)/MAPK and nuclear factor κB pathways through activating apoptosis signaling regulating kinase1.[31] In addition, doxorubicin metabolites increase ROS through suppressing ion-dependent pumps of mitochondria and sarcolemma.[27],[32] Studies revealed that cardiotoxicity of doxorubicin is dose-dependent.[29] Increase of ROS induces matrix metalloprotease(MMP) activation in cardiomyocytes which cause their subsequent death.[33] MMP activation is an event that occur in early doxorubicin-induced cardiotoxicity and indicates the development of various pathophysiological conditions such as congestive HF and reperfusion injury.[34] In fact, multifactorial mechanisms can induce cardiotoxicity in cancer patients who receive chemotherapy[Figure1].
Figure1: Reactive oxygen species act as stimulus to tumor necrosis receptor associated factor, nuclear factor κB and Ras pathway. These pathways signal cell death and apoptosis through DNA damages or activating caspase 9 or 12 which leads to cell death. Reactive oxygen species cause apoptosis by membrane changes of lipoperoxidase. The effect of reactive oxygen species on tumor necrosis receptor associated factor activates calcium ion signaling pathway, leads to mitochondrial dysfunction, results into mitochondrial damage and finally leads to cardiac dysfunction. Reactive oxygen species contribute to sarcoplasmic reticulum Ca2+ depletion in cardiac myocytes and adenosine triphosphate ase function and cause mitochondrial and cardiac dysfunction

Click here to view

Cardiac mitochondria dysfunction

Mitochondria dysfunction occurs as a result of changes in homeostasis, Ca +2 signaling, increase in ROS level, and apoptosis. Changes in homeostasis induce the opening of mitochondrial permeability transition which may lead to mitochondrial membrane potential loss, increase in ROS generation, ATP reduction, Ca +2 release in intracellular space, and mitochondria swell.[35] Several chemotherapy agents lead to thrombosis development, endothelial damage, platelet aggregation, and thrombus formation.[36] Alkylating agents can cause vascular coronary endothelial injuries which lead to intracapillary microthrombi formation.[37] Interleukin-2(IL-2) is a chemotherapy agent that can induce vasoactive mediators release and cause coronary vasospasm.[38] High-dose IL-2 is used for metastatic renal cell carcinoma, metastatic melanoma and immune checkpoint inhibitors.[39] 5-FU is used for various types of solid tumors and is associated with coronary ischemia and reversible vasospasm which might happen as a result of its effect on smooth muscle cells of cardiac vessels tone through molecular signaling pathways.[40] The endothelium dysfunction produces endothelin-1(ET-1), angiotensin II, thromboxane A2, and ROS which can lead to coagulation cascade activation through the binding of tissue factor leading to venous thrombosis and platelets aggregation.[41] Several chemotherapy agents such as arsenic trioxide, bevacizumab, and trastuzumab cause mitochondrial dysfunction leading to cardiomyocytes death.[30] A number of chemotherapy agents can lead to harmful events such as platelets aggregation and catalytic enzymes dissociation resulting into endoplasmic reticulum stress and autophagy through mechanisms modifying oxidative/nitrative proteins of cardiac mitochondria.[26] Imatinib inhibit protein kinase C(pkC) expression [42] which is a tumor-promoting receptor and an oncoprotein. In several trials, using pkC inhibitors worsened the patient's outcome.[43] Studies showed that imatinib can activate pathological hypertrophic signaling pathways by changing intracellular Ca 2+dynamics which finally can lead to myocytes apoptosis.[44] Chemotherapy agents such as antimetabolites can induce arrhythmias through coronary vasospasm by direct toxic effects on vascular endothelial through pkC activation. The latter increases as a result of nitric oxide synthase and thrombosis through decreasing fibrin lytic activity.[27],[45]

  Biomarkers in Detecting Induced Cardiotoxicity Top

Biochemistry biomarkers

Troponin is a good biomarker in detecting patients who receive chemotherapy agents and who might be at high risk of cardiomyopathy.[46] The golden standard, highly sensitive, and specific method for the detection of doxorubicin-induced cardiotoxicity is by endomyocardial biopsy of the right ventricle.[47] Good biomarkers in detecting acute doxorubicin-induced myocardial injury in chemotherapy patients include troponinT and plasma levels of circulating natriuretic peptides, such as atrial-type and brain-type natriuretic peptides(BNP).[48],[49] Myeloperoxidase(MPO) is an enzyme produced in neutrophils and can cause lipid peroxidation in proinflammatory oxidation. Measuring MPO and troponin can be a predictive indicator in estimating cardiotoxicity in chemotherapy patients.[50],[51] Several promising studies showed that high-sensitivity C-reactive protein(hs-CRP) can be a valuable biomarker for estimating trastuzumab-induced cardiotoxicity in HER2-positive breast cancer, especially in early stages.[52] Micro-RNAs(MiRs) are potent biomarkers whose alteration in their expression can be good diagnostic and prognostic biomarkers in detecting cardiotoxicity in early stages.[53] MiR-532-3p, miR-216b, miR-34c, and miR-146a were suggested to be potential regulators of doxorubicin cardiac complications, therefore evaluating their expression can be useful in predicting induced cardiac complications. MiR-320a overexpression enhanced apoptosis, aggravated the vessels in the heart and caused cardiac dysfunction.[54],[55] Plasma MiR-1,-29b, and-499 are specifically increased in anthracycline chemotherapy and this may be an alarm for acute cardiac injury situation.[56] Cytokines can be predictive biomarkers in chemotherapy-induced cardiotoxicity; for instance, doxorubicin can induce TNF-α, IL-6 generation, inducible nitric oxide synthase expression while decreasing IL-10 production.[57] We categorized and summarized the biomarkers in [Table 1].
Table 1: Diagnostic and prognostic biomarkers in chemotherapy-induced cardiotoxicity

Click here to view

Genetic markers

Genetic makers are informative in predicting pharmacogenetic effects and can be used in estimating induced cardiotoxicity; however, validating genetic variants is crucial in predicting cardiotoxicity. Several studies showed that iron levels can enhance ROS in response to anthracyclines. Therefore, patients who carry hemochromatosis gene mutation C282Y [62] are at higher risk of myocardial injuries than noncarriers who receive chemotherapy. Studies showed that patients carrying rs1883112 of nicotinamide adenine dinucleotide phosphate(NADPH) oxidase(Nox) gene are at greater risk of chronic anthracycline-induced cardiotoxicity.[63] Anthracycline can cause mitochondrial respiratory defect and lead to cardiomyopathy.[64] Doxorubicin attenuates ET-1 expression in chemotherapy patients and decrease cardiomyocytes survival signals. Therefore, estimating ET-1 expression can be a cardiomyocytes survival indicator in chemotherapy patients.[47] Nox polymorphisms are associated with doxorubicin-induced cardiotoxicity. Nox2-derived ROS is an important agent in doxorubicin-induced cardiac dysfunction which causes significant modifications in the activity and expression of MMP-9 and profibrotic genes such as procollagen IIIαI. Changes in Nox activity, oxidative/nitrosative stress, and inflammatory cell infiltration are useful indicators in predicting ROS production and risk of chemotherapy-induced cardiotoxicity.[65] Several studies revealed that RAC2 and CYBA genotypes of Nox subunits were significantly associated with anthracycline-induced cardiotoxicity.[66]RAC2 gene variant rs13058338 is associated to delayed thrombocytopenia recovery).[67] Several pharmacogenetic studies suggested that variants such as RARG rs2229774, SLC28A3 rs7853758 and UGT1A6* 4 rs17863783 are considerable variants in childhood cancer patients who are under doxorubicin therapy.[68]

Echocardiographic techniques

Recently, strain and strain rate imaging became a major technique in estimating myocardial function.[69] Strain imaging helps to better understand the pathophysiology of myocardial function.[70] Using echocardiographic techniques such as deformation imaging is crucial in the diagnosis and prognosis of cardiotoxicity events at early stages.[71] In addition, cardiac magnetic resonance imaging is a precise technique for estimating myocardial function in pathologic situations.[72] A study on chemotherapy patients with breast cancer, systolic longitudinal myocardial strain and troponin I seemed to be useful in predicting cardiotoxicity at early stages.[73] Echocardiography and myocardial velocity measurements are useful in the detection of myocardial deformation. In fact, studies suggested that Doppler-based myocardial deformation imaging is a good technique in cardiac function monitoring during chemotherapy.[74],[75] Anthracycline-induced early deterioration of the left ventricular(LV) longitude and studies suggested that early changes in global longitudinal strain can be a good prognostic marker in estimating cardiotoxicity in chemotherapy patients. Therefore, using three-dimensional speckle tracking echocardiography(3D-STE) is a valuable method.[76] The latter technique is also used for early detection of subtle LV myocardial dysfunction on ventricular and atrial levels in anthracycline-induced cardiotoxicity in leukemia.[77]

Conclusions and future perspectives

Cardiotoxicity is one of the most important side effects of chemotherapy agents in cancer patients. Cardiotoxicity may increase the mortality of cancer patients and decrease the quality of their life. Cardiotoxicity needs to be managed through diagnosis and treatment at early stages. Unfortunately, the diagnostic profile is not exactly clear and diagnosis is based on functional impairments. Diagnostic tests which are commonly used for detecting induced cardiotoxicity in cancer patients are cTn, BNP; B and NT-proBNP, NPs and hs-CRP with cTn, BNP; B and NPs together being stronger predictive biomarkers at early stages. Current studies suggest that MiRs such as miR-532-3p, miR-216b, miR-34c, miR-146a, miR-320a, miR-1, miR-29b, and miR-499 are potent biomarkers in detecting cardiotoxicity at early stages. Recent GWAS studies suggested that a number of genes and polymorphisms are predictive in estimating chemotherapy-induced cardiotoxicity. For instance, patients who carry C282Y mutation in hemochromatosis gene are at higher risk of myocardial injuries when they receive a chemotherapy agent. In addition, Nox Polymorphisms RARG rs2229774, SLC28A3 rs7853758, and UGT1A6* 4 rs17863783 are considerable variants in childhood cancer patients which should be considered in children chemotherapy. Studies suggested that SNPs for cytochrome P450 gene such as CYP3A4, CYP3A5, and CYP2C8 might have an important association with cardiotoxicity.

The first type of chemotherapy agents leads to intracellular calcium increase, therefore, we hypothesize that finding a method to detect and evaluate intracellular calcium can be a valuable diagnostic biomarker in detecting the damage at early stages. In addition, if ROS levels are detected and estimated in chemotherapy, we might be able to detect cardiotoxicity in very early stages. We suggest that MMPs should also be studied as early diagnostic biomarkers because we expect changes in MMPS and ATPase expression using chemotherapy agents that affect mitochondria. Finally, we suggest that choosing the profile of biomarkers according to the type of the chemotherapy agent used can predict cardiotoxicity at earlier stages. Finding a method to evaluate ROS and intracellular Ca +2 will allow to estimate cardiotoxicity occurrence during or after chemotherapy. Finally, a number of chemotherapy agents lead to DNA damage and affect P53, Fas, FasL, and JNK; hence, we hypothesize that some patients might have polymorphisms or mutations which make them more susceptible to induced cardiotoxicity. Therefore, GWAS studies are very valuable in future medicine. Echocardiographic techniques such as STE, 3D-STE are strong techniques in detecting induced cardiotoxicity. Nowadays, a combination of biochemical biomarkers and new techniques are needed for detecting myocardial function to manage induced cardiotoxicity at early stages and decrease chemotherapy-induced cardiac mortality.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Compliance with ethical standards

This article Compliance with ethical standards.


We wish to thank all our colleagues in Golestan Hospital clinical research development unit, Ahvaz Jundishapur University of Medical Sciences. Moreover, we thank Meysam Neisi MA of Computer Software engineering from Azad University of Sousangerd, Islamic republic of Iran, who designed the figure in Photoshop.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Shahrabi S, Azizidoost S, Shahjahani M, Rahim F, Ahmadzadeh A, Saki N, et al. New insights in cellular and molecular aspects of BM niche in chronic myelogenous leukemia. Tumour Biol 2014;35:10627-33.  Back to cited text no. 1
Truong J, Yan AT, Cramarossa G, Chan KK. Chemotherapy-induced cardiotoxicity: Detection, prevention, and management. Can J Cardiol 2014;30:869-78.  Back to cited text no. 2
Economopoulou P, Kotsakis A, Kapiris I, Kentepozidis N. Cancer therapy and cardiovascular risk: Focus on bevacizumab. Cancer Manag Res 2015;7:133-43.  Back to cited text no. 3
Ewer MS, Lippman SM. Type II chemotherapy-related cardiac dysfunction: Time to recognize a new entity. J Clin Oncol 2005;23:2900-2.  Back to cited text no. 4
Rezaeeyan H, Hassani SN, Barati M, Shahjahani M, Saki N. PD-1/PD-L1 as a prognostic factor in leukemia. J Hematopathol 2017;10:17.  Back to cited text no. 5
Glass CK, Mitchell RN. Winning the battle, but losing the war: Mechanisms and morphology of cancer-therapy-associated cardiovascular toxicity. Cardiovasc Pathol 2017;30:55-63.  Back to cited text no. 6
Tocchetti CG, Cadeddu C, Di Lisi D, Femminò S, Madonna R, Mele D, et al. From molecular mechanisms to clinical management of antineoplastic drug-induced cardiovascular toxicity: A Translational overview. Antioxid Redox Signal 2017;24:e3-e11.  Back to cited text no. 7
Mihalcea DJ, Florescu M, Vinereanu D. Mechanisms and genetic susceptibility of chemotherapy-induced cardiotoxicity in patients with breast cancer. Am J Ther 2017;24:e3-e11.  Back to cited text no. 8
Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: Incidence, treatment and prevention. Drug Saf 2000;22:263-302.  Back to cited text no. 9
Curigliano G, Cardinale D, Suter T, Plataniotis G, de Azambuja E, Sandri MT, et al. Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy: ESMO Clinical Practice Guidelines. Ann Oncol 2012;23 Suppl 7:vii155-66.  Back to cited text no. 10
Paola M, Luca F, Iris P, Chemotherapy-induced cardio toxicity in breast cancer survivors. J Gynecol Obstet 2017;1:008.  Back to cited text no. 11
Bovelli D, Plataniotis G, Roila F, ESMO Guidelines Working Group. Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO Clinical Practice Guidelines. Ann Oncol 2010;21 Suppl 5:v277-82.  Back to cited text no. 12
Cardinale D, Biasillo G, Salvatici M, Sandri MT, Cipolla CM. Using biomarkers to predict and to prevent cardiotoxicity of cancer therapy. Expert Rev Mol Diagn 2017;17:245-56.  Back to cited text no. 13
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;114:2474-81.  Back to cited text no. 14
Altena R, Perik PJ, van Veldhuisen DJ, de Vries EG, Gietema JA. Cardiovascular toxicity caused by cancer treatment: Strategies for early detection. Lancet Oncol 2009;10:391-9.  Back to cited text no. 15
Leong SL, Chaiyakunapruk N, Lee SW. Candidate gene association studies of anthracycline-induced cardiotoxicity: A Systematic review and meta-analysis. Sci Rep 2017;7:39.  Back to cited text no. 16
Pabinger I, Ay C, Dunkler D, Thaler J, Reitter EM, Marosi C, et al. Factor V leiden mutation increases the risk for venous thromboembolism in cancer patients – Results from the Vienna Cancer and Thrombosis Study (CATS). J Thromb Haemost 2015;13:17-22.  Back to cited text no. 17
Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol 2009;27:4839-47.  Back to cited text no. 18
Kucher N, Spirk D, Baumgartner I, Mazzolai L, Korte W, Nobel D, et al. Lack of prophylaxis before the onset of acute venous thromboembolism among hospitalized cancer patients: The SWIss Venous ThromboEmbolism Registry (SWIVTER). Ann Oncol 2010;21:931-5.  Back to cited text no. 19
Gran OV, Smith EN, Brækkan SK, Jensvoll H, Solomon T, Hindberg K, et al. Joint effects of cancer and variants in the factor 5 gene on the risk of venous thromboembolism. Haematologica 2016;101:1046-53.  Back to cited text no. 20
Chokshi S, Jacox J, Hull SC, Sanft T. The heartaches of cancer therapy: Acute and late cardiotoxicity in cancer survivors. Oncology (Williston Park) 2016;30:1095-8.  Back to cited text no. 21
Gomes M, Khorana AA. Risk assessment for thrombosis in cancer. In: Seminars in Thrombosis and Hemostasis. New York, USA: Thieme Medical Publishers; 2014.  Back to cited text no. 22
Brown DI, Griendling KK. Regulation of signal transduction by reactive oxygen species in the cardiovascular system. Circ Res 2015;116:531-49.  Back to cited text no. 23
Bertacchini J, Heidari N, Mediani L, Capitani S, Shahjahani M, Ahmadzadeh A, et al. Targeting PI3K/AKT/mTOR network for treatment of leukemia. Cell Mol Life Sci 2015;72:2337-47.  Back to cited text no. 24
Wang Y, Zhang Y, Sun B, Tong Q, Ren L. Rutin protects against pirarubicin-induced cardiotoxicity through TGF-β1-p38 MAPK signaling pathway. Evid Based Complement Alternat Med 2017;2017:1759385.  Back to cited text no. 25
Varga ZV, Ferdinandy P, Liaudet L, Pacher P. Mitochondria in cardiovascular physiology and disease: Drug-induced mitochondrial dysfunction and cardiotoxicity. Am J Physiol Heart Circ Physiol 2015;309:H1453.  Back to cited text no. 26
Tamargo J, Caballero R, Delpón E. Cancer chemotherapy and cardiac arrhythmias: A review. Drug Saf 2015;38:129-52.  Back to cited text no. 27
El Chemaly A, Nunes P, Jimaja W, Castelbou C, Demaurex N. Hv1 proton channels differentially regulate the pH of neutrophil and macrophage phagosomes by sustaining the production of phagosomal ROS that inhibit the delivery of vacuolar ATPases. J Leukoc Biol 2014;95:827-39.  Back to cited text no. 28
Gharib MI, Burnett AK. Chemotherapy-induced cardiotoxicity: Current practice and prospects of prophylaxis. Eur J Heart Fail 2002;4:235-42.  Back to cited text no. 29
Varga ZV, Ferdinandy P, Liaudet L, Pacher P. Drug-induced mitochondrial dysfunction and cardiotoxicity. Am J Physiol Heart Circ Physiol 2015;309:H1453-67.  Back to cited text no. 30
Angsutararux P, Luanpitpong S, Issaragrisil S. Chemotherapy-induced cardiotoxicity: Overview of the roles of oxidative stress. Oxid Med Cell Longev 2015;2015:795602.  Back to cited text no. 31
Zhao Y, Miriyala S, Miao L, Mitov M, Schnell D, Dhar SK, et al. Redox proteomic identification of HNE-bound mitochondrial proteins in cardiac tissues reveals a systemic effect on energy metabolism after doxorubicin treatment. Free Radic Biol Med 2014;72:55-65.  Back to cited text no. 32
Chan BY, Hughes BG, Roczkowsky A, de Souza P, Armanious G, Young HS, et al. Myocardial matrix metalloproteinase-2 activation impairs amplitude and frequency of spontaneous intracellular Ca2+transients in doxorubicin cardiotoxicity. FASEB J 2016;30 (1 Suppl):742.6.  Back to cited text no. 33
Bai P, Mabley JG, Liaudet L, Virág L, Szabó C, Pacher P, et al. Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity. Oncol Rep 2004;11:505-8.  Back to cited text no. 34
Canta A, Pozzi E, Carozzi VA. Mitochondrial dysfunction in chemotherapy-induced peripheral neuropathy (CIPN). Toxics 2015;3:198-223.  Back to cited text no. 35
Ramot Y, Nyska A, Spectre G. Drug-induced thrombosis: An update. Drug Saf 2013;36:585-603.  Back to cited text no. 36
Mozos I, Borzak G, Caraba A, Mihaescu R. Arterial stiffness in hematologic malignancies. Onco Targets Ther 2017;10:1381-8.  Back to cited text no. 37
Spella M, Giannou AD, Stathopoulos GT. Switching off malignant pleural effusion formation-fantasy or future? J Thorac Dis 2015;7:1009-20.  Back to cited text no. 38
Alva A, Daniels GA, Wong MK, Kaufman HL, Morse MA, McDermott DF, et al. Contemporary experience with high-dose interleukin-2 therapy and impact on survival in patients with metastatic melanoma and metastatic renal cell carcinoma. Cancer Immunol Immunother 2016;65:1533-44.  Back to cited text no. 39
Ben-Yakov M, Mattu A, Brady WJ, Dubbs SB. Prinzmetal angina (Coronary vasospasm) associated with 5-fluorouracil chemotherapy. Am J Emerg Med 2017;35:1038.e3.  Back to cited text no. 40
Di Lisi D, Madonna R, Zito C, Bronte E, Badalamenti G, Parrella P, et al. Anticancer therapy-induced vascular toxicity: VEGF inhibition and beyond. Int J Cardiol 2017;227:11-7.  Back to cited text no. 41
Sawyer TK, Wu JC, Sawyer JR, English JM. Protein kinase inhibitors: Breakthrough medicines and the next generation. Expert Opin Investig Drugs 2013;22:675-8.  Back to cited text no. 42
Newton AC, Brognard J. Reversing the paradigm: Protein kinase C as a tumor suppressor. Trends Pharmacol Sci 2017;38:438-47.  Back to cited text no. 43
Barr LA, Makarewich CA, Berretta RM, Gao H, Troupes CD, Woitek F, et al. Imatinib activates pathological hypertrophy by altering myocyte calcium regulation. Clin Transl Sci 2014;7:360-7.  Back to cited text no. 44
Markman TM, Nazarian S. Arrhythmia and electrophysiological effects of chemotherapy: A Review. Oncology 2016;91:61-8.  Back to cited text no. 45
Nolan MT, Lowenthal RM, Venn A, Marwick TH. Chemotherapy-related cardiomyopathy: A neglected aspect of cancer survivorship. Intern Med J 2014;44:939-50.  Back to cited text no. 46
Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL, et al. Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol 2012;52:1213-25.  Back to cited text no. 47
Atas E, Kismet E, Kesik V, Karaoglu B, Aydemir G, Korkmazer N, et al. Cardiac troponin-I, brain natriuretic peptide and endothelin-1 levels in a rat model of doxorubicin-induced cardiac injury. J Cancer Res Ther 2015;11:882-6.  Back to cited text no. 48
Cao L, Zhu W, Wagar EA, Meng QH. Biomarkers for monitoring chemotherapy-induced cardiotoxicity. Crit Rev Clin Lab Sci 2017;54:87-101.  Back to cited text no. 49
Singh D, Thakur A, Tang WH. Utilizing cardiac biomarkers to detect and prevent chemotherapy-induced cardiomyopathy. Curr Heart Fail Rep 2015;12:255-62.  Back to cited text no. 50
Ky B, Putt M, Sawaya H, French B, Januzzi JL Jr., Sebag IA, et al. Early increases in multiple biomarkers predict subsequent cardiotoxicity in patients with breast cancer treated with doxorubicin, taxanes, and trastuzumab. J Am Coll Cardiol 2014;63:809-16.  Back to cited text no. 51
Onitilo AA, Engel JM, Stankowski RV, Liang H, Berg RL, Doi SA, et al. High-sensitivity C-reactive protein (hs-CRP) as a biomarker for trastuzumab-induced cardiotoxicity in HER2-positive early-stage breast cancer: A pilot study. Breast Cancer Res Treat 2012;134:291-8.  Back to cited text no. 52
Holmgren G, Synnergren J, Andersson CX, Lindahl A, Sartipy P. MicroRNAs as potential biomarkers for doxorubicin-induced cardiotoxicity. ToxicolIn Vitro 2016;34:26-34.  Back to cited text no. 53
Yin Z, Zhao Y, Li H, Yan M, Zhou L, Chen C, et al. MiR-320a mediates doxorubicin-induced cardiotoxicity by targeting VEGF signal pathway. Aging (Albany NY) 2016;8:192-207.  Back to cited text no. 54
Wang JX, Zhang XJ, Feng C, Sun T, Wang K, Wang Y, et al. MicroRNA-532-3p regulates mitochondrial fission through targeting apoptosis repressor with caspase recruitment domain in doxorubicin cardiotoxicity. Cell Death Dis 2015;6:e1677.  Back to cited text no. 55
Leger KJ, Leonard D, de Lemos JA, Nielson D, Mammen PP, Winick NJ. Plasma microRNAs: Novel markers of cardiotoxicity in children undergoing anthracycline chemotherapy. Am Soc Clin Oncol 2014;32 (15 Suppl):10083.  Back to cited text no. 56
Pecoraro M, Del Pizzo M, Marzocco S, Sorrentino R, Ciccarelli M, Iaccarino G, et al. Inflammatory mediators in a short-time mouse model of doxorubicin-induced cardiotoxicity. Toxicol Appl Pharmacol 2016;293:44-52.  Back to cited text no. 57
Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011;32:2999-3054.  Back to cited text no. 58
Hayakawa H, Komada Y, Hirayama M, Hori H, Ito M, Sakurai M. Plasma levels of natriuretic peptides in relation to doxorubicin-induced cardiotoxicity and cardiac function in children with cancer. Pediatr Blood Cancer 2001;37:4-9.  Back to cited text no. 59
Lenihan DJ, Stevens PL, Massey M, Plana JC, Araujo DM, Fanale MA, et al. The utility of point-of-care biomarkers to detect cardiotoxicity during anthracycline chemotherapy: A Feasibility study. J Card Fail 2016;22:433-8.  Back to cited text no. 60
Chaudhari U, Nemade H, Gaspar JA, Hescheler J, Hengstler JG, Sachinidis A, et al. MicroRNAs as early toxicity signatures of doxorubicin in human-induced pluripotent stem cell-derived cardiomyocytes. Arch Toxicol 2016;90:3087-98.  Back to cited text no. 61
Akam-Venkata J, Franco VI, Lipshultz SE. Late cardiotoxicity: Issues for childhood cancer survivors. Curr Treat Options Cardiovasc Med 2016;18:47.  Back to cited text no. 62
Vejpongsa P, Yeh ET. Prevention of anthracycline-induced cardiotoxicity: Challenges and opportunities. J Am Coll Cardiol 2014;64:938-45.  Back to cited text no. 63
Barry E, Alvarez JA, Scully RE, Miller TL, Lipshultz SE. Anthracycline-induced cardiotoxicity: Course, pathophysiology, prevention and management. Expert Opin Pharmacother 2007;8:1039-58.  Back to cited text no. 64
Zhao Y, McLaughlin D, Robinson E, Harvey AP, Hookham MB, Shah AM, et al. Nox2 NADPH oxidase promotes pathologic cardiac remodeling associated with Doxorubicin chemotherapy. Cancer Res 2010;70:9287-97.  Back to cited text no. 65
Reichwagen A, Ziepert M, Kreuz M, Gödtel-Armbrust U, Rixecker T, Poeschel V, et al. Association of NADPH oxidase polymorphisms with anthracycline-induced cardiotoxicity in the RICOVER-60 trial of patients with aggressive CD20(+) B-cell lymphoma. Pharmacogenomics 2015;16:361-72.  Back to cited text no. 66
Megías-Vericat JE, Montesinos P, Herrero MJ, Moscardó F, Bosó V, Rojas L, et al. Impact of NADPH oxidase functional polymorphisms in acute myeloid leukemia induction chemotherapy. Pharmacogenomics J 2017:1-7. [Epub ahead of print].  Back to cited text no. 67
Aminkeng F, Ross CJ, Rassekh SR, Hwang S, Rieder MJ, Bhavsar AP, et al. Recommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicity. Br J Clin Pharmacol 2016;82:683-95.  Back to cited text no. 68
Sutherland GR, Di Salvo G, Claus P, D'hooge J, Bijnens B. Strain and strain rate imaging: A new clinical approach to quantifying regional myocardial function. J Am Soc Echocardiogr 2004;17:788-802.  Back to cited text no. 69
Gorcsan J 3rd, Tanaka H. Echocardiographic assessment of myocardial strain. J Am Coll Cardiol 2011;58:1401-13.  Back to cited text no. 70
Thavendiranathan P, Poulin F, Lim KD, Plana JC, Woo A, Marwick TH, et al. Use of myocardial strain imaging by echocardiography for the early detection of cardiotoxicity in patients during and after cancer chemotherapy: A systematic review. J Am Coll Cardiol 2014;63:2751-68.  Back to cited text no. 71
Mangion K, McComb C, Auger DA, Epstein FH, Berry C. Magnetic resonance imaging of myocardial strain after acute ST-segment-elevation myocardial infarction: A Systematic review. Circ Cardiovasc Imaging 2017;10: pii: e006498.  Back to cited text no. 72
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;5:596-603.  Back to cited text no. 73
Jurcut R, Wildiers H, Ganame J, D'hooge J, De Backer J, Denys H, et al. Strain rate imaging detects early cardiac effects of pegylated liposomal Doxorubicin as adjuvant therapy in elderly patients with breast cancer. J Am Soc Echocardiogr 2008;21:1283-9.  Back to cited text no. 74
Stoodley PW, Richards DA, Hui R, Boyd A, Harnett PR, Meikle SR, et al. Two-dimensional myocardial strain imaging detects changes in left ventricular systolic function immediately after anthracycline chemotherapy. Eur J Echocardiogr 2011;12:945-52.  Back to cited text no. 75
Tang Q, Jiang Y, Xu Y, Xia H. Speckle tracking echocardiography predicts early subclinical anthracycline cardiotoxicity in patients with breast cancer. J Clin Ultrasound 2017;45:222-30.  Back to cited text no. 76
Abd MM, Salah Z, Abbas S, ELKaffas R, Hamza H, Abdul HH, et al. Early identification of subtle left ventricular and atrial dysfunction among asymptomatic survivors of childhood myeloid leukemia: Insights from the novel three-dimensional speckle tracking echocardiography. Thorac Cardiovasc Surg 2017;65(Suppl 2):EPP25.  Back to cited text no. 77



  [Table 1]

This article has been cited by
1 Evaluating the Risk Factors and Induced Cardiotoxicity in Breast Cancer Patients
Habib Haybar,Sasan Razmjoo,Samira Razaghi,Mitra Ranjbaran
Jundishapur Journal of Chronic Disease Care. 2021; In Press(In Press)
[Pubmed] | [DOI]
2 Cyclin D1: A Golden Gene in Cancer, Cardiotoxicity, and Cardioprotection
Habib Haybar,Mehhdi Shahrouzian,Zahra Gatavizadeh,Najmaldin Saki,Mahmood Maniati,Zeinab Deris Zayeri
Jundishapur Journal of Chronic Disease Care. 2021; In Press(In Press)
[Pubmed] | [DOI]
3 Effect of Rosuvastatin in Preventing Chemotherapy-Induced Cardiotoxicity in Women With Breast Cancer: A Randomized, Single-Blind, Placebo-Controlled Trial
Maryam Nabati,Ghasem Janbabai,Jamil Esmailian,Jamshid Yazdani
Journal of Cardiovascular Pharmacology and Therapeutics. 2019; 24(3): 233
[Pubmed] | [DOI]
4 Strategies to inhibit arsenic trioxide-induced cardiotoxicity in acute promyelocytic leukemia
Habib Haybar,Saeid Shahrabi,Hadi Rezaeeyan,Hosein Jodat,Najmaldin Saki
Journal of Cellular Physiology. 2019;
[Pubmed] | [DOI]
5 Strategies to increase cardioprotection through cardioprotective chemokines in chemotherapy-induced cardiotoxicity
Habib Haybar,Saeid Shahrabi,Zeinab Deris Zayeri,SeyedmohammadSadegh Pezeshki
International Journal of Cardiology. 2018;
[Pubmed] | [DOI]
6 Chronic myeloid leukemia with complex karyotypes: Prognosis and therapeutic approaches
Ali Amin Asnafi,Zeinab Deris Zayeri,Saeid Shahrabi,Kazem Zibara,Tina Vosughi
Journal of Cellular Physiology. 2018;
[Pubmed] | [DOI]
7 A novel infram deletion in MSH6 gene in glioma: Conversation on MSH6 mutations in brain tumors
Zeinab Deris Zayeri,Maryam Tahmasebi Birgani,Javad Mohammadi Asl,Davood Kashipazha,Mohammadreza Hajjari
Journal of Cellular Physiology. 2018;
[Pubmed] | [DOI]


Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

  In this article
Why Cardiac Issu...
Biomarkers in De...
Article Figures
Article Tables

 Article Access Statistics
    PDF Downloaded38    
    Comments [Add]    
    Cited by others 7    

Recommend this journal