Cardiovascular Damage Induced by Radiotherapy

  • Antonio Galvano
  • Giuseppina NovoEmail author
  • Mario Roselli
  • Antonio Giordano
  • Antonio Russo
Part of the Current Clinical Pathology book series (CCPATH)


Radiotherapy is a fundamental therapeutic aid that in recent years has contributed significantly to improve the prognosis of cancer patients. Despite its great effectiveness, it can cause a wide spectrum of toxic effects. Among these, cardiovascular toxicity is very relevant, and it can occur even many years after the termination of treatment. The concomitant use of radiotherapy with other antineoplastic drugs, including new-generation tyrosine-kinase inhibitors or immunotherapy, can enhance its cardiotoxic effects. It is fundamental to know the cardiovascular toxic effects that are potentially linked to radiotherapy (RIHD: radiation-induced heart damage), to monitor patients who underwent radiotherapy in order to prevent their occurrence and to early detect and treat patients eventually experiencing this complications. In this chapter, we will review the main clinical conditions which can affect the cardiovascular system after radiotherapy, trying to provide some suggestions about the management of the cardiologic patient at risk or burdened by RIHD.


RIHD Radiotherapy Oncology Biomarkers Management 


  1. 1.
  2. 2.
    Specht L, Yahalom J, Illidge T, Berthelsen AK, Constine LS, Eich HT, et al. Modern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG). Int J Radiat Oncol Biol Phys. 2014;89(4):854–62.CrossRefGoogle Scholar
  3. 3.
    Ng AK, Bernardo MP, Weller E, Backstrand KH, Silver B, Marcus KC, et al. Long-term survival and competing causes of death in patients with early-stage Hodgkin’s disease treated at age 50 or younger. J Clin Oncol. 2002;20(8):2101–8.CrossRefGoogle Scholar
  4. 4.
    Mulrooney DA, Yeazel MW, Kawashima T, Mertens AC, Mitby P, Stovall M, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ. 2009;339:b4606.CrossRefGoogle Scholar
  5. 5.
    Swerdlow AJ, Higgins CD, Smith P, Cunningham D, Hancock BW, Horwich A, et al. Myocardial infarction mortality risk after treatment for Hodgkin disease: a collaborative British cohort study. J Natl Cancer Inst. 2007;99(3):206–14.CrossRefGoogle Scholar
  6. 6.
    Boivin JF, Hutchison GB, Lubin JH, Mauch P. Coronary artery disease mortality in patients treated for Hodgkin’s disease. Cancer. 1992;69(5):1241–7.CrossRefGoogle Scholar
  7. 7.
    Hancock SL, Tucker MA, Hoppe RT. Factors affecting late mortality from heart disease after treatment of Hodgkin’s disease. JAMA. 1993;270(16):1949–55.CrossRefGoogle Scholar
  8. 8.
    Hardenbergh PH, Munley MT, Bentel GC, Kedem R, Borges-Neto S, Hollis D, et al. Cardiac perfusion changes in patients treated for breast cancer with radiation therapy and doxorubicin: preliminary results. Int J Radiat Oncol Biol Phys. 2001;49(4):1023–8.CrossRefGoogle Scholar
  9. 9.
    Gyenes G, Fornander T, Carlens P, Glas U, Rutqvist LE. Detection of radiation-induced myocardial damage by technetium-99m sestamibi scintigraphy. Eur J Nucl Med. 1997;24(3):286–92.PubMedPubMedCentralGoogle Scholar
  10. 10.
    Darby SC, Ewertz M, McGale P, Bennet AM, Blom-Goldman U, Brønnum D, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987–98.CrossRefGoogle Scholar
  11. 11.
    Zinzani PL, Gherlinzoni F, Piovaccari G, Frezza G, Bendandi M, Ferretti RM, et al. Cardiac injury as late toxicity of mediastinal radiation therapy for Hodgkin’s disease patients. Haematologica. 1996;81(2):132–7.PubMedGoogle Scholar
  12. 12.
    Shimizu Y, Kodama K, Nishi N, Kasagi F, Suyama A, Soda M, et al. Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki atomic bomb survivor data, 1950-2003. BMJ. 2010;340:b5349.CrossRefGoogle Scholar
  13. 13.
    Le Gallic C, Phalente Y, Manens L, Dublineau I, Benderitter M, Gueguen Y, et al. Chronic internal exposure to low dose 137Cs induces positive impact on the stability of atherosclerotic plaques by reducing inflammation in ApoE−/− mice. PLoS One. 2015;10(6):e0128539.CrossRefGoogle Scholar
  14. 14.
    Linton MF, Babaev VR, Huang J, Linton EF, Tao H, Yancey PG. Macrophage apoptosis and efferocytosis in the pathogenesis of atherosclerosis. Circ J. 2016;80(11):2259–68.CrossRefGoogle Scholar
  15. 15.
    Van Der Meeren A, Squiban C, Gourmelon P, Lafont H, Gaugler MH. Differential regulation by IL-4 and IL-10 of radiation-induced IL-6 and IL-8 production and ICAM-1 expression by human endothelial cells. Cytokine. 1999;11(11):831–8.CrossRefGoogle Scholar
  16. 16.
    Rodemann HP, Bamberg M. Cellular basis of radiation-induced fibrosis. Radiother Oncol. 1995;35(2):83–90.CrossRefGoogle Scholar
  17. 17.
    Bhattacharya S, Asaithamby A. Ionizing radiation and heart risks. Semin Cell Dev Biol. 2016;58:14–25.CrossRefGoogle Scholar
  18. 18.
    Wang Y, Boerma M, Zhou D. Ionizing radiation-induced endothelial cell senescence and cardiovascular diseases. Radiat Res. 2016;186(2):153–61.CrossRefGoogle Scholar
  19. 19.
    Korpela E, Liu SK. Endothelial perturbations and therapeutic strategies in normal tissue radiation damage. Radiat Oncol. 2014;9:266.CrossRefGoogle Scholar
  20. 20.
    Yarnold J, Brotons MC. Pathogenetic mechanisms in radiation fibrosis. Radiother Oncol. 2010;97(1):149–61.CrossRefGoogle Scholar
  21. 21.
    Nadlonek NA, Weyant MJ, Yu JA, Cleveland JC Jr, Reece TB, Meng X, et al. Radiation induces osteogenesis in human aortic valve interstitial cells. J Thorac Cardiovasc Surg. 2012;144(6):1466–70.CrossRefGoogle Scholar
  22. 22.
    Mulrooney DA, Armstrong GT, Huang S, Ness KK, Ehrhardt MJ, Joshi VM, et al. Cardiac outcomes in adult survivors of childhood cancer exposed to cardiotoxic therapy: a cross-sectional study. Ann Intern Med. 2016;164(2):93–101.CrossRefGoogle Scholar
  23. 23.
    Lancellotti P, Nkomo VT, Badano LP, Bergler-Klein J, Bogaert J, Davin L, et al. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr. 2013;26(9):1013–32.CrossRefGoogle Scholar
  24. 24.
    Veinot JP, Edwards WD. Pathology of radiation-induced heart disease: a surgical and autopsy study of 27 cases. Hum Pathol. 1996;27(8):766–73.CrossRefGoogle Scholar
  25. 25.
    Chello M, Mastroroberto P, Romano R, Zofrea S, Bevacqua I, Marchese AR. Changes in the proportion of types I and III collagen in the left ventricular wall of patients with post-irradiative pericarditis. Cardiovasc Surg. 1996;4(2):222–6.CrossRefGoogle Scholar
  26. 26.
    Fidler MM, , Reulen RC, Henson K, Kelly J, Cutter D, Levitt GA, et al. Population-based long-term cardiac-specific mortality among 34,489 five-year survivors of childhood cancer in Great Britain. Circulation 2017;135(10):951–963.CrossRefGoogle Scholar
  27. 27.
    Heidenreich PA, , Schnittger I, Strauss HW, Vagelos RH, Lee BK, Mariscal CS, et al. Screening for coronary artery disease after mediastinal irradiation for Hodgkin’s disease. J Clin Oncol 2007;25(1):43–49.CrossRefGoogle Scholar
  28. 28.
    Orzan F, Brusca A, Conte MR, Presbitero P, Figliomeni MC. Severe coronary artery disease after radiation therapy of the chest and mediastinum: clinical presentation and treatment. Br Heart J. 1993;69(6):496–500.CrossRefGoogle Scholar
  29. 29.
    Caro-Codón J, Jiménez-Valero S, Galeote G, Sanchez-Recalde A, Moreno R. Radiation-induced coronary artery disease: useful insights from OCT. Int J Cardiol. 2016;202:535–6.CrossRefGoogle Scholar
  30. 30.
    Cheng RK, , Lee MS, Seki A, Shemin RJ, Cruz D, Lluri G, et al. Radiation coronary arteritis refractory to surgical and percutaneous revascularization culminating in orthotopic heart transplantation. Cardiovasc Pathol 2013;22(4):303–308.CrossRefGoogle Scholar
  31. 31.
    Amromin GD, Gildenhorn HL, Solomon RD, Nadkarni BB. The synergism of X-irradiation and cholesterol-fat feeding on the development of coronary artery lesions. J Atheroscler Res. 1964;4:325–34.CrossRefGoogle Scholar
  32. 32.
    Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of hodgkin lymphoma treated with radiation therapy. JAMA. 2003;290(21):2831–7.CrossRefGoogle Scholar
  33. 33.
    Marks LB, Yu X, Prosnitz RG, Zhou SM, Hardenbergh PH, Blazing M, et al. The incidence and functional consequences of RT-associated cardiac perfusion defects. Int J Radiat Oncol Biol Phys. 2005;63(1):214–23.CrossRefGoogle Scholar
  34. 34.
    Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366(9503):2087–106.CrossRefGoogle Scholar
  35. 35.
    Wu W, Masri A, Popovic ZB, Smedira NG, Lytle BW, Marwick TH, et al. Long-term survival of patients with radiation heart disease undergoing cardiac surgery: a cohort study. Circulation. 2013;127(14):1476–85.CrossRefGoogle Scholar
  36. 36.
    de Waard DE, Verhorst PM, Visser CA. Exercise-induced syncope as late consequence of radiotherapy. Int J Cardiol. 1996;57(3):289–91.CrossRefGoogle Scholar
  37. 37.
    Lee PJ, Mallik R. Cardiovascular effects of radiation therapy: practical approach to radiation therapy-induced heart disease. Cardiol Rev. 2005;13(2):80–6.CrossRefGoogle Scholar
  38. 38.
    Gharagozloo F, Clements IP, Mullany CJ. Use of the internal mammary artery for myocardial revascularization in a patient with radiation-induced coronary artery disease. Mayo Clin Proc. 1992;67(11):1081–4.CrossRefGoogle Scholar
  39. 39.
    Chang AS, Smedira NG, Chang CL, Benavides MM, Myhre U, Feng J, et al. Cardiac surgery after mediastinal radiation: extent of exposure influences outcome. J Thorac Cardiovasc Surg. 2007;133(2):404–13.CrossRefGoogle Scholar
  40. 40.
    Andratschke N, , Maurer J, Molls M, Trott KR. Late radiation-induced heart disease after radiotherapy. Clinical importance, radiobiological mechanisms and strategies of prevention. Radiother Oncol 2011;100(2):160–166.CrossRefGoogle Scholar
  41. 41.
    Carmel RJ, Kaplan HS. Mantle irradiation in Hodgkin’s disease. An analysis of technique, tumor eradication, and complications. Cancer. 1976;37(6):2813–25.CrossRefGoogle Scholar
  42. 42.
    Carver JR, Shapiro CL, Ng A, Jacobs L, Schwartz C, Virgo KS, et al. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol. 2007;25(25):3991–4008.CrossRefGoogle Scholar
  43. 43.
    Morton DL, Glancy DL, Joseph WL, Adkins PC. Management of patients with radiation-induced pericarditis with effusion: a note on the development of aortic regurgitation in two of them. Chest. 1973;64(3):291–7.CrossRefGoogle Scholar
  44. 44.
    Arsenian MA. Cardiovascular sequelae of therapeutic thoracic radiation. Prog Cardiovasc Dis. 1991;33(5):299–311.CrossRefGoogle Scholar
  45. 45.
    Imazio M, Brucato A, Mayosi BM, Derosa FG, Lestuzzi C, Macor A, et al. Medical therapy of pericardial diseases: part II: noninfectious pericarditis, pericardial effusion and constrictive pericarditis. J Cardiovasc Med (Hagerstown). 2010;11(11):785–94.Google Scholar
  46. 46.
    Neughebauer B, Alvarez V, Harb T, Keefer M. Constrictive pericarditis caused by candida glabrata in an immunocompetent patient: case report and review of literature. Scand J Infect Dis. 2002;34(8):615–9.CrossRefGoogle Scholar
  47. 47.
    Ling LH, Oh JK, Schaff HV, Danielson GK, Mahoney DW, Seward JB, et al. Constrictive pericarditis in the modern era: evolving clinical spectrum and impact on outcome after pericardiectomy. Circulation. 1999;100(13):1380–6.CrossRefGoogle Scholar
  48. 48.
    Bertog SC, Thambidorai SK, Parakh K, Schoenhagen P, Ozduran V, Houghtaling PL, et al. Constrictive pericarditis: etiology and cause-specific survival after pericardiectomy. J Am Coll Cardiol. 2004;43(8):1445–52.CrossRefGoogle Scholar
  49. 49.
    Brosius FC, Waller BF, Roberts WC. Radiation heart disease. Analysis of 16 young (aged 15 to 33 years) necropsy patients who received over 3,500 rads to the heart. Am J Med. 1981;70(3):519–30.CrossRefGoogle Scholar
  50. 50.
    Bijl JM, Roos MM, van Leeuwen-Segarceanu EM, Vos JM, Bos WW, Biesma DH, et al. Assessment of valvular disorders in survivors of Hodgkin's lymphoma treated by mediastinal radiotherapy ± chemotherapy. Am J Cardiol. 2016;117(4):691–6.CrossRefGoogle Scholar
  51. 51.
    Cuomo JR, Sharma GK, Conger PD, Weintraub NL. Novel concepts in radiation-induced cardiovascular disease. World J Cardiol. 2016;8(9):504–19.CrossRefGoogle Scholar
  52. 52.
    Heidenreich PA, Hancock SL, Lee BK, Mariscal CS, Schnittger I. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol. 2003;42(4):743–9.CrossRefGoogle Scholar
  53. 53.
    Katz NM, Hall AW, Cerqueira MD. Radiation induced valvulitis with late leaflet rupture. Heart. 2001;86(6):E20.CrossRefGoogle Scholar
  54. 54.
    Crestanello JA, McGregor CG, Danielson GK, Daly RC, Dearani JA, Orszulak TA, et al. Mitral and tricuspid valve repair in patients with previous mediastinal radiation therapy. Ann Thorac Surg. 2004;78(3):826–31. discussion 826–31CrossRefGoogle Scholar
  55. 55.
    Carlson RG, Mayfield WR, Normann S, Alexander JA. Radiation-associated valvular disease. Chest. 1991;99(3):538–45.CrossRefGoogle Scholar
  56. 56.
    Slama MS, Le Guludec D, Sebag C, Leenhardt AR, Davy JM, Pellerin DE, et al. Complete atrioventricular block following mediastinal irradiation: a report of six cases. Pacing Clin Electrophysiol. 1991;14(7):1112–8.CrossRefGoogle Scholar
  57. 57.
    La Vecchia L. Physiologic dual chamber pacing in radiation-induced atrioventricular block. Chest. 1996;110(2):580–1.CrossRefGoogle Scholar
  58. 58.
    Constine LS, Schwartz RG, Savage DE, King V, Muhs A. Cardiac function, perfusion, and morbidity in irradiated long-term survivors of Hodgkin's disease. Int J Radiat Oncol Biol Phys. 1997;39(4):897–906.CrossRefGoogle Scholar
  59. 59.
    Tolba KA, Deliargyris EN. Cardiotoxicity of cancer therapy. Cancer Investig. 1999;17(6):408–22.CrossRefGoogle Scholar
  60. 60.
    Handa N, McGregor CG, Daly RC, Dearani JA, Edwards BS, Frantz RP, et al. Heart transplantation for radiation-associated end-stage heart failure. Transpl Int. 2000;13(2):162–5.CrossRefGoogle Scholar
  61. 61.
    Al-Kindi SG, Oliveira GH. Heart transplantation outcomes in radiation-induced restrictive cardiomyopathy. J Card Fail. 2016;22(6):475–8.CrossRefGoogle Scholar
  62. 62.
    Cheng SW, Ting AC, Lam LK, Wei WI. Carotid stenosis after radiotherapy for nasopharyngeal carcinoma. Arch Otolaryngol Head Neck Surg. 2000;126(4):517–21.CrossRefGoogle Scholar
  63. 63.
    Lam WW, Leung SF, So NM, Wong KS, Liu KH, Ku PK, et al. Incidence of carotid stenosis in nasopharyngeal carcinoma patients after radiotherapy. Cancer. 2001;92(9):2357–63.CrossRefGoogle Scholar
  64. 64.
    O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med. 1999;340(1):14–22.CrossRefGoogle Scholar
  65. 65.
    King LJ, Hasnain SN, Webb JA, Kingston JE, Shafford EA, Lister TA, et al. Asymptomatic carotid arterial disease in young patients following neck radiation therapy for Hodgkin lymphoma. Radiology. 1999;213(1):167–72.CrossRefGoogle Scholar
  66. 66.
    Gurm HS, Yadav JS, Fayad P, Katzen BT, Mishkel GJ, Bajwa TK, et al. Long-term results of carotid stenting versus endarterectomy in high-risk patients. N Engl J Med. 2008;358(15):1572–9.CrossRefGoogle Scholar
  67. 67.
    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.CrossRefGoogle Scholar
  68. 68.
    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.CrossRefGoogle Scholar
  69. 69.
    Bedir A, et al. Serum troponin I as an early marker in determining radiotherapy-induced cardiac damage. Basic Sci Res J Med Clin. 2012:51–9.Google Scholar
  70. 70.
    D'Errico MP, Grimaldi L, Petruzzelli MF, Gianicolo EA, Tramacere F, Monetti A, et al. N-terminal pro-B-type natriuretic peptide plasma levels as a potential biomarker for cardiac damage after radiotherapy in patients with left-sided breast cancer. Int J Radiat Oncol Biol Phys. 2012;82(2):e239–46.CrossRefGoogle Scholar
  71. 71.
    Mazzola RN, Levra G, Alongi F. Radiation dose-response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma. J Clin Oncol. 2016;34(24):2940–1.CrossRefGoogle Scholar
  72. 72.
    Maraldo MV, Brodin NP, Vogelius IR, Aznar MC, Munck Af Rosenschöld P, Petersen PM, et al. Risk of developing cardiovascular disease after involved node radiotherapy versus mantle field for Hodgkin lymphoma. Int J Radiat Oncol Biol Phys. 2012;83(4):1232–7.CrossRefGoogle Scholar
  73. 73.
    Lettmaier S, et al. Radiation exposure of the heart, lung and skin by radiation therapy for breast cancer: a dosimetric comparison between partial breast irradiation using multicatheter brachytherapy and whole breast teletherapy. Radiother Oncol. 2011;100(2):189–94.CrossRefGoogle Scholar
  74. 74.
    Maraldo MV, Specht L. A decade of comparative dose planning studies for early-stage Hodgkin lymphoma: what can we learn? Int J Radiat Oncol Biol Phys. 2014;90(5):1126–35.CrossRefGoogle Scholar
  75. 75.
    Hoppe BS, Flampouri S, Su Z, Morris CG, Latif N, Dang NH, et al. Consolidative involved-node proton therapy for stage IA-IIIB mediastinal Hodgkin lymphoma: preliminary dosimetric outcomes from a phase II study. Int J Radiat Oncol Biol Phys. 2012;83(1):260–7.CrossRefGoogle Scholar
  76. 76.
    Hoppe BS, Flampouri S, Su Z, Latif N, Dang NH, Lynch J, et al. Effective dose reduction to cardiac structures using protons compared with 3DCRT and IMRT in mediastinal Hodgkin lymphoma. Int J Radiat Oncol Biol Phys. 2012;84(2):449–55.CrossRefGoogle Scholar
  77. 77.
    Aznar MC, Maraldo MV, Schut DA, Lundemann M, Brodin NP, Vogelius IR, et al. Minimizing late effects for patients with mediastinal Hodgkin lymphoma: deep inspiration breath-hold, IMRT, or both? Int J Radiat Oncol Biol Phys. 2015;92(1):169–74.CrossRefGoogle Scholar
  78. 78.
    Gagliardi G, Constine LS, Moiseenko V, Correa C, Pierce LJ, Allen AM, et al. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys. 2010;76(3 Suppl):S77–85.CrossRefGoogle Scholar
  79. 79.
    Taunk NK, Haffty BG, Kostis JB, Goyal S. Radiation-induced heart disease: pathologic abnormalities and putative mechanisms. Front Oncol. 2015;5:39. Scholar
  80. 80.
    Lancellotti P, Nkomo VT. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. Eur Heart J Cardiovasc Imaging. 2013;14(8):721–40. Scholar

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Antonio Galvano
    • 1
  • Giuseppina Novo
    • 2
    Email author
  • Mario Roselli
    • 3
  • Antonio Giordano
    • 4
  • Antonio Russo
    • 1
  1. 1.Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of PalermoPalermoItaly
  2. 2.Division of CardiologyBiomedical Department of Internal Medicine and Specialities (DIBIMIS), University of PalermoPalermoItaly
  3. 3.Department of Systems Medicine, Medical OncologyPoliclinico Tor Vergata Biospecimen Cancer Repository, University of Rome Tor VergataRomeItaly
  4. 4.Department of Biology, College of Science and Technology, Temple UniversitySbarro Health Research Organization, Inc.PhiladelphiaUSA

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