Abstract
The incidence of cardiovascular disorders is one of the most concerns among people who underwent cancer therapy. The heart side effects of cancer therapy may occur during treatment to some years after the end of treatment. Some epidemiological studies confirm that heart diseases are one of the most common reasons for mortality among patients that were received treatment for cancer. Experimental studies and also clinical investigations indicate that inflammatory changes such as pericarditis, myocarditis, and also fibrosis are key mechanisms of cardiac diseases following chemotherapy/radiotherapy. It seems that chronic oxidative stress, massive cell death, and chronic overproduction of pro-inflammatory and pro-fibrosis cytokines are the key mechanisms of cardiovascular diseases following cancer therapy. Furthermore, infiltration of inflammatory cells and upregulation of some enzymes such as NADPH Oxidases are a hallmark of heart diseases after cancer therapy. In the current review, we aim to explain how radiation or chemotherapy can induce inflammatory and fibrosis-related diseases in the heart. We will explain the cellular and molecular mechanisms of cardiac inflammation and fibrosis following chemo/radiation therapy, and then review some adjuvants to reduce the risk of inflammation and fibrosis in the heart.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10787-021-00894-9/MediaObjects/10787_2021_894_Fig1_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10787-021-00894-9/MediaObjects/10787_2021_894_Fig2_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10787-021-00894-9/MediaObjects/10787_2021_894_Fig3_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs10787-021-00894-9/MediaObjects/10787_2021_894_Fig4_HTML.png)
Similar content being viewed by others
Data availability
No new data generated.
References
Aisenberg AC (1999) Problems in Hodgkin’s disease management. Blood 93(3):761–779
Alanazi AM, Fadda L, Alhusaini A, Ahmad R, Hasan IH, Mahmoud AM (2020) Liposomal resveratrol and/or carvedilol attenuate doxorubicin-induced cardiotoxicity by modulating inflammation, oxidative stress and S100A1 in rats. Antioxidants 9(2):159
Alhazzani K, Alotaibi MR, Alotaibi FN, Aljerian K, As Sobeai HM, Alhoshani AR, Alanazi AZ, Alanazi WA, Alswayyed M (2021) Protective effect of valsartan against doxorubicin-induced cardiotoxicity: histopathology and metabolomics in vivo study. J Biochem Mol Toxicol 35(9):22842
Armenian SH, Armstrong GT, Aune G, Chow EJ, Ehrhardt MJ, Ky B, Moslehi J, Mulrooney DA, Nathan PC, Ryan TD, van der Pal HJ, van Dalen EC, Kremer LCM (2018) Cardiovascular disease in survivors of childhood cancer: insights into epidemiology, pathophysiology, and prevention. J Clin Oncol 36(21):2135–2144
Arunachalam S, Nagoor Meeran MF, Azimullah S, Sharma C, Goyal SN, Ojha S (2021) Nerolidol attenuates oxidative stress, inflammation, and apoptosis by modulating Nrf2/MAPK signaling pathways in doxorubicin-induced acute cardiotoxicity in rats. Antioxidants 10(6):984
Aryafar T, Amini P, Rezapoor S, Shabeeb D, Eleojo Musa A, Najafi M, Shirazi A (2020) Modulation of radiation-induced NADPH oxidases in rat’s heart tissues by melatonin. J Biomed Phys Eng 11(4):465–472
Bache Robert J, Chen Y (2014) NOX2-induced myocardial fibrosis and diastolic dysfunction. J Am Coll Cardiol 63(24):2742–2744
Basavaraju SR, Easterly CE (2002) Pathophysiological effects of radiation on atherosclerosis development and progression, and the incidence of cardiovascular complications. Med Phys 29(10):2391–2403
Baselet B, Sonveaux P, Baatout S, Aerts A (2019) Pathological effects of ionizing radiation: endothelial activation and dysfunction. Cell Mol Life Sci 76(4):699–728
Borthwick LA (2016) The IL-1 cytokine family and its role in inflammation and fibrosis in the lung. Semin Immunopathol 38(4):517–534
Bouillon K, Haddy N, Delaloge S, Garbay J-R, Garsi J-P, Brindel P, Mousannif A, Lê MG, Labbe M, Arriagada R (2011) Long-term cardiovascular mortality after radiotherapy for breast cancer. J Am Coll Cardiol 57(4):445–452
Bradshaw PT, Stevens J, Khankari N, Teitelbaum SL, Neugut AI, Gammon MD (2016) Cardiovascular disease mortality among breast cancer survivors. Epidemiology 27(1):6–13
Cappetta D, Esposito G, Piegari E, Russo R, Ciuffreda LP, Rivellino A, Berrino L, Rossi F, De Angelis A, Urbanek K (2016) SIRT1 activation attenuates diastolic dysfunction by reducing cardiac fibrosis in a model of anthracycline cardiomyopathy. Int J Cardiol 205:99–110
Cervelli T, Panetta D, Navarra T, Andreassi MG, Basta G, Galli A, Salvadori PA, Picano E, Del Turco S (2014) Effects of single and fractionated low-dose irradiation on vascular endothelial cells. Atherosclerosis 235(2):510–518
Chang SH, Lee KJ, Koo H (2004) The radioprotective effect and mechanism of captopril on radiation induced-heart damage in rats. Radiat Oncol J 22(1):40–54
Chang A, Nasti TH, Khan MK, Parashar S, Kaufman JL, Boise LH, Lonial S, Ahmed R, Nooka AK (2018) Myocarditis with radiotherapy and immunotherapy in multiple myeloma. J Oncol Pract 14(9):561–564
Chen L, Yan K-P, Liu X-C, Wang W, Li C, Li M, Qiu C-G (2018) Valsartan regulates TGF-β/Smads and TGF-β/p38 pathways through lncRNA CHRF to improve doxorubicin-induced heart failure. Arch Pharmacal Res 41(1):101–109
Cheng D, Chen L, Tu W, Wang H, Wang Q, Meng L, Li Z, Yu Q (2020) Protective effects of valsartan administration on doxorubicin-induced myocardial injury in rats and the role of oxidative stress and NOX2/NOX4 signaling. Mol Med Rep 22(5):4151–4162
Chera BS, Rodriguez C, Morris CG, Louis D, Yeung D, Li Z, Mendenhall NP (2009) Dosimetric comparison of three different involved nodal irradiation techniques for stage II Hodgkin’s lymphoma patients: conventional radiotherapy, intensity-modulated radiotherapy, and three-dimensional proton radiotherapy. Int J Radiat Oncol Biol Phys 75(4):1173–1180
Chiabrando JG, Bonaventura A, Vecchié A, Wohlford GF, Mauro AG, Jordan JH, Grizzard JD, Montecucco F, Berrocal DH, Brucato A, Imazio M, Abbate A (2020) Management of acute and recurrent pericarditis: JACC state-of-the-art review. J Am Coll Cardiol 75(1):76–92
Cho BJ, Feld R, Leighl N, Opitz I, Anraku M, Tsao M-S, Hwang DM, Hope A, de Perrot M (2014) A feasibility study evaluating Surgery for Mesothelioma After Radiation Therapy: the “SMART” approach for resectable malignant pleural mesothelioma. J Thorac Oncol 9(3):397–402
Choi SH, Kim M, Lee HJ, Kim EH, Kim CH, Lee YJ (2016) Effects of NOX1 on fibroblastic changes of endothelial cells in radiation-induced pulmonary fibrosis. Mol Med Rep 13(5):4135–4142
Christidi E, Brunham LR (2021) Regulated cell death pathways in doxorubicin-induced cardiotoxicity. Cell Death Dis 12(4):339
Cinamon G, Grabovsky V, Winter E, Franitza S, Feigelson S, Shamri R, Dwir O, Alon R (2001) Novel chemokine functions in lymphocyte migration through vascular endothelium under shear flow. J Leukoc Biol 69(6):860–866
Collins-Underwood JR, Zhao W, Sharpe JG, Robbins ME (2008) NADPH oxidase mediates radiation-induced oxidative stress in rat brain microvascular endothelial cells. Free Radical Biol Med 45(6):929–938
Conklin KA (2000) Dietary antioxidants during cancer chemotherapy: impact on chemotherapeutic effectiveness and development of side effects. Nutr Cancer 37:1–18
Conklin KA (2005) Coenzyme q10 for prevention of anthracycline-induced cardiotoxicity. Integr Cancer Ther 4(2):110–130
Cui Q, Wang J-Q, Assaraf YG, Ren L, Gupta P, Wei L, Ashby CR Jr, Yang D-H, Chen Z-S (2018) Modulating ROS to overcome multidrug resistance in cancer. Drug Resist Updates 41:1–25
da Silva RMFL (2019) Effects of radiotherapy in coronary artery disease. Curr Atheroscler Rep 21(12):1–8
De Ruysscher D, Faivre-Finn C, Nackaerts K, Jordan K, Arends J, Douillard J-Y, Ricardi U, Peters S (2020) Recommendation for supportive care in patients receiving concurrent chemotherapy and radiotherapy for lung cancer. Ann Oncol 31(1):41–49
Dhesi S, Chu MP, Blevins G, Paterson I, Larratt L, Oudit GY, Kim DH (2013) Cyclophosphamide-induced cardiomyopathy: a case report, review, and recommendations for management. J Investig Med High Impact Case Rep 1(1):2324709613480346–2324709613480346
Dorn GW 2nd (2009) Apoptotic and non-apoptotic programmed cardiomyocyte death in ventricular remodelling. Cardiovasc Res 81(3):465–473
Fan Z, Han Y, Ye Y, Liu C, Cai H (2017) l-carnitine preserves cardiac function by activating p38 MAPK/Nrf2 signalling in hearts exposed to irradiation. Eur J Pharmacol 804:7–12
Farhood B, Aliasgharzadeh A, Amini P, Saffar H, Motevaseli E, Rezapoor S, Nouruzi F, Shabeeb D, Musa AE, Ashabi G, Mohseni M, Moradi H, Najafi M (2019a) Radiation-induced dual oxidase upregulation in rat heart tissues: protective effect of melatonin. Medicina (lithuania) 55(7):317
Farhood B, Goradel NH, Mortezaee K, Khanlarkhani N, Salehi E, Nashtaei MS, Shabeeb D, Musa AE, Fallah H, Najafi M (2019b) Intercellular communications-redox interactions in radiation toxicity; potential targets for radiation mitigation. J Cell Commun Signal 13(1):3–16
Farhood B, Ashrafizadeh M, Khodamoradi E, Hoseini-Ghahfarokhi M, Afrashi S, Musa AE, Najafi M (2020a) Targeting of cellular redox metabolism for mitigation of radiation injury. Life Sci 250:117570
Farhood B, Hoseini-Ghahfarokhi M, Motevaseli E, Mirtavoos-Mahyari H, Musa AE, Najafi M (2020b) TGF-β in radiotherapy: mechanisms of tumor resistance and normal tissues injury. Pharmacol Res 155:104745
Frey MK, Arfsten H, Pavo N, Han E, Kastl S, Hülsmann M, Gyöngyösi M, Bergler-Klein J (2021) Sacubitril/valsartan is well tolerated in patients with longstanding heart failure and history of cancer and improves ventricular function: real-world data. Cardio-Oncology 7(1):35
Fu X, Tang J, Wen P, Huang Z, Najafi M (2021) Redox interactions-induced cardiac toxicity in cancer therapy. Arch Biochem Biophys 708:108952
Fubini B, Hubbard A (2003) Reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation by silica in inflammation and fibrosis. Free Radical Biol Med 34(12):1507–1516
Fung C, Fossa SD, Milano MT, Sahasrabudhe DM, Peterson DR, Travis LB (2015) Cardiovascular disease mortality after chemotherapy or surgery for testicular nonseminoma: a population-based study. J Clin Oncol 33(28):3105–3115
Gibb AA, Lazaropoulos MP, Elrod JW (2020) Myofibroblasts and fibrosis: mitochondrial and metabolic control of cellular differentiation. Circ Res 127(3):427–447
González A, Schelbert EB, Díez J, Butler J (2018) Myocardial interstitial fibrosis in heart failure: biological and translational perspectives. J Am Coll Cardiol 71(15):1696–1706
Group EBCTC (2000) Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 355(9217):1757–1770
Hatch M, Cardis E (2017) Somatic health effects of chernobyl: 30 years on. Eur J Epidemiol 32(12):1047–1054
Haubner F, Ohmann E, Pohl F, Prantl L, Strutz J, Gassner HG (2013) Effects of radiation on the expression of adhesion molecules and cytokines in a static model of human dermal microvascular endothelial cells. Clin Hemorheol Microcirc 54(4):371–379
He H, Luo Y, Qiao Y, Zhang Z, Yin D, Yao J, You J, He M (2018) Curcumin attenuates doxorubicin-induced cardiotoxicity via suppressing oxidative stress and preventing mitochondrial dysfunction mediated by 14-3-3γ. Food Funct 9(8):4404–4418
Huang G, Pan S-T (2020) ROS-mediated therapeutic strategy in chemo-/radiotherapy of head and neck cancer. Oxid Med Cell Longev. https://doi.org/10.1155/2020/5047987
Huang S, Che J, Chu Q, Zhang P (2020) The role of NLRP3 inflammasome in radiation-induced cardiovascular injury. Front Cell Develop Biol 8:140
Iborra-Egea O, Gálvez-Montón C, Roura S, Perea-Gil I, Prat-Vidal C, Soler-Botija C, Bayes-Genis A (2017) Mechanisms of action of sacubitril/valsartan on cardiac remodeling: a systems biology approach. NPJ Syst Biol Appl 3:12–12
Ibrahim MA, Ashour OM, Ibrahim YF, El-Bitar HI, Gomaa W, Abdel-Rahim SR (2009) Angiotensin-converting enzyme inhibition and angiotensin AT(1)-receptor antagonism equally improve doxorubicin-induced cardiotoxicity and nephrotoxicity. Pharmacol Res 60(5):373–381
Imaizumi M, Furukawa K, Ohishi W, Hida A (2018) Thyroid diseases among atomic bomb survivors. Radiat Prot Dosimetry 182(1):62–66
Imanaka-Yoshida K (2020) Inflammation in myocardial disease: from myocarditis to dilated cardiomyopathy. Pathol Int 70(1):1–11
Jia L-X, Qi G-M, Liu O, Li T-T, Yang M, Cui W, Zhang W-M, Qi Y-F, Du J (2013) Inhibition of platelet activation by clopidogrel prevents hypertension-induced cardiac inflammation and fibrosis. Cardiovasc Drugs Ther 27(6):521–530
Katamura M, Iwai-Kanai E, Nakaoka M, Okawa Y, Ariyoshi M, Mita Y, Nakamura A, Ikeda K, Ogata T, Ueyama T (2014) Curcumin attenuates doxorubicin-induced cardiotoxicity by inducing autophagy via the regulation of JNK phosphorylation. J Clin Exp Cardiolog 5(09):1–8
Kelly DJ, Cox AJ, Gow RM, Zhang Y, Kemp BE, Gilbert RE (2004) Platelet-derived growth factor receptor transactivation mediates the trophic effects of angiotensin II in vivo. Hypertension 44(2):195–202
Khaled S, Gupta KB, Kucik DF (2012) Ionizing radiation increases adhesiveness of human aortic endothelial cells via a chemokine-dependent mechanism. Radiat Res 177(5):594–601
Khan R, Sheppard R (2006) Fibrosis in heart disease: understanding the role of transforming growth factor-beta in cardiomyopathy, valvular disease and arrhythmia. Immunology 118(1):10–24
Khodamoradi E, Hoseini-Ghahfarokhi M, Amini P, Motevaseli E, Shabeeb D, Musa AE, Najafi M, Farhood B (2020) Targets for protection and mitigation of radiation injury. Cell Mol Life Sci 77(16):3129–3159
Kim Y-J, Ko H, Park J-S, Han I-H, Amor EC, Lee JW, Yang HO (2010) Dimethyl cardamonin inhibits lipopolysaccharide-induced inflammatory factors through blocking NF-κB p65 activation. Int Immunopharmacol 10(9):1127–1134
Kim M, Choi SH, ** YB, Lee HJ, Ji YH, Kim J, Lee YS, Lee YJ (2013) The effect of oxidized low-density lipoprotein (ox-LDL) on radiation-induced endothelial-to-mesenchymal transition. Int J Radiat Biol 89(5):356–363
Kingery JR, Hamid T, Lewis RK, Ismahil MA, Bansal SS, Rokosh G, Townes TM, Ildstad ST, Jones SP, Prabhu SD (2017) Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure. Basic Res Cardiol 112(2):19
Kolivand S, Amini P, Saffar H, Rezapoor S, Motevaseli E, Najafi M, Nouruzi F, Shabeeb D, Musa AE (2019) Evaluating the radioprotective effect of curcumin on rat’s heart tissues. Curr Radiopharm 12(1):23–28
Kovacic JC, Dimmeler S, Harvey RP, Finkel T, Aikawa E, Krenning G, Baker AH (2019) Endothelial to mesenchymal transition in cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol 73(2):190–209
Lavine KJ, Pinto AR, Epelman S, Kopecky BJ, Clemente-Casares X, Godwin J, Rosenthal N, Kovacic JC (2018) The macrophage in cardiac homeostasis and disease: JACC macrophage in CVD series (part 4). J Am Coll Cardiol 72(18):2213–2230
Lee Y, Gustafsson AB (2009) Role of apoptosis in cardiovascular disease. Apoptosis 14(4):536–548
Lin J, Fang L, Li H, Li Z, Lyu L, Wang H, **ao J (2019) Astragaloside IV alleviates doxorubicin induced cardiomyopathy by inhibiting NADPH oxidase derived oxidative stress. Eur J Pharmacol 859:172490
Lipshultz SE, Rifai N, Dalton VM, Levy DE, Silverman LB, Lipsitz SR, Colan SD, Asselin BL, Barr RD, Clavell LA, Hurwitz CA, Moghrabi A, Samson Y, Schorin MA, Gelber RD, Sallan SE (2004) The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 351(2):145–153
Little MP, Azizova TV, Hamada N (2021) Low-and moderate-dose non-cancer effects of ionizing radiation in directly exposed individuals, especially circulatory and ocular diseases: a review of the epidemiology. Int J Radiat Biol 97(6):782–803
Liu G, Liu Y, Wang R, Hou T, Chen C, Zheng S, Dong Z (2016) Spironolactone attenuates doxorubicin-induced cardiotoxicity in rats. Cardiovasc Ther 34(4):216–224
Liu LK, Ouyang W, Zhao X, Su SF, Yang Y, Ding WJ, Luo DX, He ZX, Lu B (2017) Pathogenesis and prevention of radiation-induced myocardial fibrosis. Asian Pac J Cancer Prev 18(3):583
Livingston K, Schlaak RA, Puckett LL, Bergom C (2020) The role of mitochondrial dysfunction in radiation-induced heart disease: from bench to bedside. Front Cardiovasc Med 7:20. https://doi.org/10.3389/fcvm.2020.00020
Ma ZG, Yuan YP, Wu HM, Zhang X, Tang QZ (2018) Cardiac fibrosis: new insights into the pathogenesis. Int J Biol Sci 14(12):1645–1657
Ma Z-G, Kong C-Y, Wu H-M, Song P, Zhang X, Yuan Y-P, Deng W, Tang Q-Z (2020a) Toll-like receptor 5 deficiency diminishes doxorubicin-induced acute cardiotoxicity in mice. Theranostics 10(24):11013–11025
Ma Z, Xu L, Liu D, Zhang X, Di S, Li W, Zhang J, Reiter RJ, Han J, Li X (2020b) Utilizing melatonin to alleviate side effects of chemotherapy: a potentially good partner for treating cancer with ageing. Oxid Med Cell Longev 2020:1
Mancilla TR, Iskra B, Aune GJ (2019) Doxorubicin-induced cardiomyopathy in children. comprehensive. Physiology 9(3):905
Marinko T (2019) Pericardial disease after breast cancer radiotherapy. Radiol Oncol 53(1):1
Martín-Garcia A, López-Fernández T, Mitroi C, Chaparro-Muñoz M, Moliner P, Martin-Garcia AC, Martinez-Monzonis A, Castro A, Lopez-Sendon JL, Sanchez PL (2020) Effectiveness of sacubitril–valsartan in cancer patients with heart failure. ESC Heart Fail 7(2):763–767
Mauch P, Kalish L, Marcus K, Shulman L, Krill E, Tarbell N, Silver B, Weinstein H, Come S, Canellos G (1995) Long-term survival in Hodgkin’s disease relative impact of mortality, second tumors, infection, and cardiovascular disease. Cancer J Sci Am 1(1):33–42
Medhora M, Gao F, Jacobs ER, Moulder JE (2012) Radiation damage to the lung: mitigation by angiotensin-converting enzyme (ACE) inhibitors. Respirology (carlton, Vic) 17(1):66–71
Meng L, Lin H, Zhang J, Lin N, Sun Z, Gao F, Luo H, Ni T, Luo W, Chi J (2019) Doxorubicin induces cardiomyocyte pyroptosis via the TINCR-mediated posttranscriptional stabilization of NLR family pyrin domain containing 3. J Mol Cell Cardiol 136:15–26
Miles A, Liaskou E, Eksteen B, Lalor PF, Adams DH (2008) CCL25 and CCL28 promote alpha4 beta7-integrin-dependent adhesion of lymphocytes to MAdCAM-1 under shear flow. Am J Physiol Gastrointest Liver Physiol 294(5):G1257-1267
Milgrom-Hoffman M, Harrelson Z, Ferrara N, Zelzer E, Evans SM, Tzahor E (2011) The heart endocardium is derived from vascular endothelial progenitors. Development (cambridge, England) 138(21):4777–4787
Min SS, Wierzbicki AS (2017) Radiotherapy, chemotherapy and atherosclerosis. Curr Opin Cardiol 32(4):441–447
Mortezaee K, Goradel NH, Amini P, Shabeeb D, Musa AE, Najafi M, Farhood B (2019a) NADPH oxidase as a target for modulation of radiation response; implications to carcinogenesis and radiotherapy. Curr Mol Pharmacol 12(1):50–60
Mortezaee K, Najafi M, Farhood B, Ahmadi A, Shabeeb D, Musa AE (2019b) NF-κB targeting for overcoming tumor resistance and normal tissues toxicity. J Cell Physiol 234(10):17187–17204
Mortezaee K, Shabeeb D, Musa AE, Najafi M, Farhood B (2019c) Metformin as a radiation modifier; implications to normal tissue protection and tumor sensitization. Curr Clin Pharmacol 14(1):41–53
Mukhopadhyay P, Rajesh M, Bátkai S, Kashiwaya Y, Hasko G, Liaudet L, Szabó C, Pacher P (2009a) Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am J Physiol-Heart Circ Physiol 296(5):H1466–H1483
Mukhopadhyay P, Rajesh M, Bátkai S, Kashiwaya Y, Haskó G, Liaudet L, Szabó C, Pacher P (2009b) Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am J Physiol Heart Circ Physiol 296(5):H1466-1483
Nabavi SM, Nabavi SF, Sureda A, **ao J, Dehpour AR, Shirooie S, Silva AS, Baldi A, Khan H, Daglia M (2019) Anti-inflammatory effects of melatonin: a mechanistic review. Crit Rev Food Sci Nutr 59(sup1):S4–S16
Najafi M, Cheki M, Amini P, Javadi A, Shabeeb D, Eleojo MA (2019) Evaluating the protective effect of resveratrol, Q10, and alpha-lipoic acid on radiation-induced mice spermatogenesis injury: a histopathological study. Int J Reprod Biomed 17(12):907–914
Najafi M, Shayesteh MRH, Mortezaee K, Farhood B, Haghi-Aminjan H (2020) The role of melatonin on doxorubicin-induced cardiotoxicity: a systematic review. Life Sci 241:117173
Nakayama H, Otsu K (2018) Mitochondrial DNA as an inflammatory mediator in cardiovascular diseases. Biochem J 475(5):839–852
Olaussen KA, Dunant A, Fouret P, Brambilla E, André F, Haddad V, Taranchon E, Filipits M, Pirker R, Popper HH (2006) DNA repair by ERCC1 in non–small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 355(10):983–991
Ongnok B, Chattipakorn N, Chattipakorn SC (2020) Doxorubicin and cisplatin induced cognitive impairment: the possible mechanisms and interventions. Exp Neurol 324:113118
Ostovaneh MR, Ambale-Venkatesh B, Fuji T, Bakhshi H, Shah R, Murthy VL, Tracy RP, Guallar E, Wu CO, Bluemke DA (2018) Association of liver fibrosis with cardiovascular diseases in the general population: the multi-ethnic study of atherosclerosis (MESA). Circulation 11(3):e007241
Palmai-Pallag T, Bachrati CZ (2014) Inflammation-induced DNA damage and damage-induced inflammation: a vicious cycle. Microbes Infect 16(10):822–832
Pao T-H, Chang W-L, Chiang N-J, Lin C-Y, Lai W-W, Tseng Y-L, Lin F-C (2020) Pericardial effusion after definitive concurrent chemotherapy and intensity modulated radiotherapy for esophageal cancer. Radiat Oncol 15(1):1–10
Parajuli N, Patel VB, Wang W, Basu R, Oudit GY (2014) Loss of NOX2 (gp91phox) prevents oxidative stress and progression to advanced heart failure. Clin Sci (london, England: 1979) 127(5):331–340
Parichatikanond W, Luangmonkong T, Mangmool S, Kurose H (2020) Therapeutic targets for the treatment of cardiac fibrosis and cancer: focusing on TGF-β signaling. Front Cardiovasc Med 7:34
Pashkow FJ (2011) Oxidative stress and inflammation in heart disease: do antioxidants have a role in treatment and/or prevention? Int J Inflam 2011:514623 https://doi.org/10.4061/2011/514623
Paszat LF, Mackillop WJ, Groome PA, Boyd C, Schulze K, Holowaty E (1998) Mortality from myocardial infarction after adjuvant radiotherapy for breast cancer in the surveillance, epidemiology, and end-results cancer registries. J Clin Oncol 16(8):2625–2631
Peretto G, Sala S, Rizzo S, De Luca G, Campochiaro C, Sartorelli S, Benedetti G, Palmisano A, Esposito A, Tresoldi M (2019) Arrhythmias in myocarditis: state of the art. Heart Rhythm 16(5):793–801
Piccioli P, Rubartelli A (2013) The secretion of IL-1β and options for release. Semin Immunol 25(6):425–429
** Z, Peng Y, Lang H, **nyong C, Zhiyi Z, **aocheng W, Hong Z, Liang S (2020) Oxidative stress in radiation-induced cardiotoxicity. Oxid Med Cell Longev 2020:3579143
Pinsky DJ, Aji W, Szabolcs M, Athan ES, Liu Y, Yang YM, Kline RP, Olson KE, Cannon PJ (1999) Nitric oxide triggers programmed cell death (apoptosis) of adult rat ventricular myocytes in culture. Am J Physiol-Heart Circ Physiol 277(3):H1189–H1199
Piroth MD, Baumann R, Budach W, Dunst J, Feyer P, Fietkau R, Haase W, Harms W, Hehr T, Krug D (2019) Heart toxicity from breast cancer radiotherapy. Strahlenther Onkol 195(1):1–12
Pohlers D, Brenmoehl J, Löffler I, Müller CK, Leipner C, Schultze-Mosgau S, Stallmach A, Kinne RW, Wolf G (2009) TGF-β and fibrosis in different organs—molecular pathway imprints. Biochimica Et Biophysica Acta (BBA) Mol Basis Dis 1792(8):746–756
Poznyak AV, Grechko AV, Orekhova VA, Khotina V, Ivanova EA, Orekhov AN (2020) NADPH oxidases and their role in atherosclerosis. Biomedicines 8(7):206
Qi W, Boliang W, **aoxi T, Guoqiang F, Jianbo X, Gang W (2020) Cardamonin protects against doxorubicin-induced cardiotoxicity in mice by restraining oxidative stress and inflammation associated with Nrf2 signaling. Biomed Pharmacother 122:109547
Ratosa I, Pantar MI (2019) Cardiotoxicity of mediastinal radiotherapy. Rep Pr Oncol Radiother 24(6):629–643
Refaat MM, Katz WE (2011) Neoplastic pericardial effusion. Clin Cardiol 34(10):593–598
Rutqvist LE, Lax I, Fornander T, Johansson H (1992) Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys 22(5):887–896
Safi M, Kanesvaran R, Alradhi M, Al-Danakh A, ** F, Al-Sabai N, Shan X, Liu J (2020) Overall survival in heart disease–related death in non-small cell lung cancer patients: nonimmunotherapy versus immunotherapy era: population-based study. Front Oncol 10:1866
Sagar S, Liu PP, Cooper LT Jr (2012) Myocarditis. Lancet 379(9817):738–747
Saleh MA, Antar SA, Hazem RM, El-Azab MF (2020) Pirfenidone and vitamin D ameliorate cardiac fibrosis induced by doxorubicin in ehrlich ascites carcinoma bearing mice: modulation of monocyte chemoattractant protein-1 and Jun N-terminal kinase-1 pathways. Pharmaceuticals 13(11):348
Schett G, Dayer J-M, Manger B (2016) Interleukin-1 function and role in rheumatic disease. Nat Rev Rheumatol 12(1):14–24
Schöllnberger H, Eidemüller M, Cullings HM, Simonetto C, Neff F, Kaiser JC (2018) Dose-responses for mortality from cerebrovascular and heart diseases in atomic bomb survivors: 1950–2003. Radiat Environ Biophys 57(1):17–29
Shaty MH, Arif IS, Al-Ezzi MI, Hanna DB (2018) Metformin attenuate fibrosis in both acute and chronic doxorubicin cardiotoxicity in rabbits. J Pharm Sci Res 10(6):1559–1565
Shi J, Abdelwahid E, Wei L (2011) Apoptosis in anthracycline cardiomyopathy. Curr Pediatr Rev 7(4):329–336
Shin H-J, Kwon H-K, Lee J-H, Gui X, Achek A, Kim J-H, Choi S (2015) Doxorubicin-induced necrosis is mediated by poly-(ADP-ribose) polymerase 1 (PARP1) but is independent of p53. Sci Rep 5(1):15798
Siwik DA, Pagano PJ, Colucci WS (2001) Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts. Am J Physiol Cell Physiol 280(1):C53-60
Spallarossa P, Altieri P, Garibaldi S, Ghigliotti G, Barisione C, Manca V, Fabbi P, Ballestrero A, Brunelli C, Barsotti A (2006) Matrix metalloproteinase-2 and -9 are induced differently by doxorubicin in H9c2 cells: the role of MAP kinases and NAD(P)H oxidase. Cardiovasc Res 69(3):736–745
Sparano JA (1999) Doxorubicin/taxane combinations: cardiac toxicity and pharmacokinetics. Semin Oncol 26(3 Suppl 9):14–19
Stewart FA, Seemann I, Hoving S, Russell NS (2013) Understanding radiation-induced cardiovascular damage and strategies for intervention. Clin Oncol (r Coll Radiol (great Br)) 25(10):617–624
Sugihara T, Hattori Y, Yamamoto Y, Qi F, Ichikawa R, Sato A, Liu MY, Abe K, Kanno M (1999) Preferential impairment of nitric oxide-mediated endothelium-dependent relaxation in human cervical arteries after irradiation. Circulation 100(6):635–641
Sun Z, Schriewer J, Tang M, Marlin J, Taylor F, Shohet RV, Konorev EA (2016) The TGF-β pathway mediates doxorubicin effects on cardiac endothelial cells. J Mol Cell Cardiol 90:129–138
Sun X, Chen G, **e Y, Jiang D, Han J, Chen F, Song Y (2020) Qiliqiangxin improves cardiac function and attenuates cardiac remodelling in doxorubicin-induced heart failure rats. Pharm Biol 58(1):417–426
Suzuki H, Wildhirt S, Dudek R, Narayan K, Bailey A, Bing R (1996) Induction of apoptosis in myocardial infarction and its possible relationship to nitric oxide synthase in macrophages. Tissue Cell 28(1):89–97
Swamy AV, Gulliaya S, Thippeswamy A, Koti BC, Manjula DV (2012) Cardioprotective effect of curcumin against doxorubicin-induced myocardial toxicity in albino rats. Indian J Pharmacol 44(1):73
Taunk NK, Haffty BG, Kostis JB, Goyal S (2015) Radiation-induced heart disease: pathologic abnormalities and putative mechanisms. Front Oncol 5:39
Thyagarajan A, Sahu RP (2018) Potential contributions of antioxidants to cancer therapy: immunomodulation and radiosensitization. Integr Cancer Ther 17(2):210–216
Tromp J, Boerman LM, Sama IE, Maass SW, Maduro JH, Hummel YM, Berger MY, de Bock GH, Gietema JA, Berendsen AJ (2020) Long-term survivors of early breast cancer treated with chemotherapy are characterized by a pro-inflammatory biomarker profile compared to matched controls. Eur J Heart Fail 22(7):1239–1246
Tsai T-H, Lin C-J, Hang C-L, Chen W-Y (2019) Calcitriol attenuates doxorubicin-induced cardiac dysfunction and inhibits endothelial-to-mesenchymal transition in mice. Cells 8(8):865
van der Veen SJ, Ghobadi G, de Boer RA, Faber H, Cannon MV, Nagle PW, Brandenburg S, Langendijk JA, van Luijk P, Coppes RP (2015) ACE inhibition attenuates radiation-induced cardiopulmonary damage. Radiother Oncol 114(1):96–103
Van Linthout S, Tschöpe C (2017) Inflammation–cause or consequence of heart failure or both? Curr Heart Fail Rep 14(4):251–265
Wang Y, Liu Q, Zhao W, Zhou X, Miao G, Sun C, Zhang H (2017) NADPH oxidase activation contributes to heavy ion irradiation-induced cell death. Dose-Response 15(1):1559325817699697
Wang B, Wang H, Zhang M, Ji R, Wei J, **n Y, Jiang X (2020a) Radiation-induced myocardial fibrosis: mechanisms underlying its pathogenesis and therapeutic strategies. J Cell Mol Med 24(14):7717–7729
Wang X, Wang Q, Li W, Zhang Q, Jiang Y, Guo D, Sun X, Lu W, Li C, Wang Y (2020b) TFEB-NF-κB inflammatory signaling axis: a novel therapeutic pathway of dihydrotanshinone I in doxorubicin-induced cardiotoxicity. J Exp Clin Cancer Res 39(1):93
Weberpals J, Jansen L, Müller OJ, Brenner H (2018) Long-term heart-specific mortality among 347 476 breast cancer patients treated with radiotherapy or chemotherapy: a registry-based cohort study. Eur Heart J 39(43):3896–3903
Weidig P, McMaster D, Bayraktutan U (2004) High glucose mediates pro-oxidant and antioxidant enzyme activities in coronary endothelial cells. Diabetes Obes Metab 6(6):432–441
West AP, Shadel GS (2017) Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat Rev Immunol 17(6):363–375
Wong FL, Yamada M, Sasaki H, Kodama K, Hosoda Y (1999) Effects of radiation on the longitudinal trends of total serum cholesterol levels in the atomic bomb survivors. Radiat Res 151(6):736–746
Wortel RC, Mizrachi A, Li H, Markovsky E, Enyedi B, Jacobi J, Brodsky O, Cao J, Lippert AR, Incrocci L, Mulhall JP, Haimovitz-Friedman A (2019) Sildenafil protects endothelial cells from radiation-induced oxidative stress. J Sex Med 16(11):1721–1733
Wu C, Lin D, Ma F, Jiang F, Wang Y (2021) New progress in elucidating the relationship between cancer therapy and cardiovascular toxicity. BioSci Trends 15(4):211–218
Yahyapour R, Amini P, Saffar H, Rezapoor S, Motevaseli E, Cheki M, Farhood B, Nouruzi F, Shabeeb D, Musa AE (2018a) Metformin protects against radiation-induced heart injury and attenuates the upregulation of dual oxidase genes following rat’s chest irradiation. Int J Mol Cell Med 7(3):193
Yahyapour R, Shabeeb D, Cheki M, Musa AE, Farhood B, Rezaeyan A, Amini P, Fallah H, Najafi M (2018b) Radiation protection and mitigation by natural antioxidants and flavonoids: Implications to radiotherapy and radiation disasters. Curr Mol Pharmacol 11(4):285–304
Yarom R, Harper IS, Wynchank S, van Schalkwyk D, Madhoo J, Williams K, Salie R, Genade S, Lochner A (1993) Effect of captopril on changes in rats’ hearts induced by long-term irradiation. Radiat Res 133(2):187–197
Yu W, Qin X, Zhang Y, Qiu P, Wang L, Zha W, Ren J (2020) Curcumin suppresses doxorubicin-induced cardiomyocyte pyroptosis via a PI3K/Akt/mTOR-dependent manner. Cardiovasc Diagn Ther 10(4):752
Yun S-M, Kim S-H, Kim E-H (2019) The molecular mechanism of transforming growth factor-β signaling for intestinal fibrosis: a mini-review. Front Pharmacol 10:162–162
Zeng C, Duan F, Hu J, Luo B, Huang B, Lou X, Sun X, Li H, Zhang X, Yin S, Tan H (2020) NLRP3 inflammasome-mediated pyroptosis contributes to the pathogenesis of non-ischemic dilated cardiomyopathy. Redox Biol 34:101523–101523
Zhang J, Lei W, Chen X, Wang S, Qian W (2018) Oxidative stress response induced by chemotherapy in leukemia treatment. Mol Clin Oncol 8(3):391–399
Zhao Y, McLaughlin D, Robinson E, Harvey AP, Hookham MB, Shah AM, McDermott BJ, Grieve DJ (2010) Nox2 NADPH oxidase promotes pathologic cardiac remodeling associated with doxorubicin chemotherapy. Can Res 70(22):9287–9297
Zorc-Pleskovic R, Alibegović A, Zorc M, Milutinović A, Radovanović N, Petrović D (2006) Apoptosis of cardiomyocytes in myocarditis. Folia Biol 52(1–2):6–9
Funding
No.
Author information
Authors and Affiliations
Contributions
All authors contributed to the preparing the first draft. MN checked the manuscript for scientific contents.
Corresponding authors
Ethics declarations
Conflict of interest
No.
Ethical approval
No human or animal study performed in this study.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Yang, R., Tan, C. & Najafi, M. Cardiac inflammation and fibrosis following chemo/radiation therapy: mechanisms and therapeutic agents. Inflammopharmacol 30, 73–89 (2022). https://doi.org/10.1007/s10787-021-00894-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10787-021-00894-9