Cardiovascular Damage Induced by Anti-VEGF Therapy

  • Giuseppina Novo
  • Daniela Di Lisi
  • Enrico Bronte
  • Manuela Fiuza
  • Fausto J. Pinto
Part of the Current Clinical Pathology book series (CCPATH)


Vascular endothelial growth factor (VEGF) plays an important role in maintaining the regular homeostasis of vascular walls. VEGF binds its receptor (VEGFR) promoting the regular survival and function of endothelial cells. Anti-VEGF and anti-VEGFR drugs inhibit the action of VEGF and VEGFR. These drugs can cause cardiovascular toxic effects such as arterial hypertension, thromboembolism, myocardial ischemia and heart failure. The monoclonal antibody bevacizumab and tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib, regorafenib, axitinib, cabozantinib, ponatinib) are the main inhibitors of VEGF, VEGFR and other tyrosine kinases. In this chapter we will illustrate the cardiovascular toxic effects of these drugs, their mechanism of action, strategy to early diagnose and treat these complications. We will also illustrate strategy to prevent cardiovascular toxicity. It is important to know cardiovascular toxic effect of these drugs widely used in oncological field, to avoid the development of severe future complications.


VEGF VEGFR Cardiac toxicity Bevacizumab Thromboembolism Vessel Vascular toxicity 


  1. 1.
    Schiffrin EL. A critical review of the role of endothelial factors in the pathogenesis of hypertension. J Cardiovasc Pharmacol. 2001;38(Suppl 2):S3–6.CrossRefGoogle Scholar
  2. 2.
    Green D, Jones H, Thijssen D, Cable NT, Atkinson G. Flow-mediated dilation and cardiovascular event prediction does nitric oxide matter? Hypertension. 2011;57:363–9.CrossRefGoogle Scholar
  3. 3.
    Park KA, Park WJ. Endothelial dysfunction: clinical complications in cardiovascular disease and therapeutic approaches. J Korean Med Sci. 2015;30:1213–25.CrossRefGoogle Scholar
  4. 4.
    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.CrossRefGoogle Scholar
  5. 5.
    Kurzyk A. Angiogenesis-possibilities, problems and perspectives. Postepy Biochem. 2015;61:25–34.PubMedGoogle Scholar
  6. 6.
    Tocchetti CG, Gallucci G, Coppola C, Piscopo G, Cipresso C, Maurea C, et al. The emerging issue of cardiac dysfunction induced by antineoplastic angiogenesis inhibitors. Eur J Heart Fail. 2013;15:482–9.CrossRefGoogle Scholar
  7. 7.
    Folkman J. Angiogenesis: an organizing principle for drug discovery? Nat Rev Drug Discov. 2007;6:273–86.CrossRefGoogle Scholar
  8. 8.
    Anisimov A, Alitalo A, Korpisalo P, Soronen J, Kaijalainen S, Leppänen VM, et al. Activated forms of VEGF-C and VEGF-D provide improved vascular function in skeletal muscle. Circ Res. 2009;104:1302–12.CrossRefGoogle Scholar
  9. 9.
    Madonna R, De Caterina R. VEGF receptor switching in heart development and disease. Cardiovasc Res. 2009;84:4–6.CrossRefGoogle Scholar
  10. 10.
    Herrmann J, Yang EH, Iliescu CA, Cilingiroglu M, Charitakis K, Hakeem A, et al. Vascular toxicities of cancer therapies: the old and the new – an evolving avenue. Circulation. 2016;133:1272–89.CrossRefGoogle Scholar
  11. 11.
    Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis. 2007;49:186–93.CrossRefGoogle Scholar
  12. 12.
    Eskens FA, Verweij J. The clinical toxicity profile of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) targeting angiogenesis inhibitors; a re-view. Eur J Cancer. 2006;42:3127–39.CrossRefGoogle Scholar
  13. 13.
    Sugrue MM, Yi J, Purdie D, et al. Serious arterial thromboembolic events (sATE) in patients (pts) with metastatic colorectal cancer (mCRC) treated with bevacizumab (BV): results from the BRiTE registry. J Clin Oncol. 2007;25(18):4136.Google Scholar
  14. 14.
    Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370:2011–9.CrossRefGoogle Scholar
  15. 15.
    Mena AC, Pulido EG, Guillen-Ponce C. Understanding the molecular-based mechanism of action of the tyrosine kinase inhibitor: sunitinib. Anti-Cancer Drugs. 2010;21(Suppl. 1):S3–11.CrossRefGoogle Scholar
  16. 16.
    Lyer R, Fetterly G, Lugade A, Thanavala Y. Sorafenib: a clinical and pharmacologic review. Expert Opin Pharmacother. 2010;11:1943–55.CrossRefGoogle Scholar
  17. 17.
    Youn JY, Wang T, Cai H. An ezrin/calpain/PI3K/AMPK/eNOSs1179 signaling cascade mediating VEGF-dependent endothelial nitric oxide production. Circ Res. 2009;104:50–9.CrossRefGoogle Scholar
  18. 18.
    Hutson TE, Davis ID, Machiels JP, De Souza PL, Rottey S, Hong BF, et al. Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2010;28:475–80.CrossRefGoogle Scholar
  19. 19.
    Van Marcke C, Ledoux B, Petit B, Seront E. Rapid and fatal acute heart failure induced by pazopanib. BMJ Case Rep. 2015;2015 pii: bcr2015211522.Google Scholar
  20. 20.
    Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol. 2013;14:552–62.CrossRefGoogle Scholar
  21. 21.
    Bronte E, Bronte G, Novo G, Bronte F, Bavetta MG, Lo Re G, et al. What links BRAF to the heart function? New insights from the cardiotoxicity of BRAF inhibitors in cancer treatment. Oncotarget. 2015;6(34):35589–601.CrossRefGoogle Scholar
  22. 22.
    Elisei R, Schlumberger MJ, Müller SP, Schöffski P, Brose MS, Shah MH, et al. Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639–46.CrossRefGoogle Scholar
  23. 23.
    Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007;96:1788–95.CrossRefGoogle Scholar
  24. 24.
    Facemire CS, Nixon AB, Griffiths R, , Hurwitz H, Coffman TM. Vascular endothelial growth factor receptor 2 controls blood pressure by regulating nitric oxide synthase expression. Hypertension 2009;54:652–658.CrossRefGoogle Scholar
  25. 25.
    Kilickap S, Abali H, Celik I. Bevacizumab, bleeding, thrombosis, and warfarin. J Clin Oncol. 2003;21:3542.CrossRefGoogle Scholar
  26. 26.
    Izzedine H, Massard C, Spano JP, Goldwasser F, Khayat D, Soria JC. VEGF signalling inhibition-induced proteinuria: mechanisms, significance and management. Eur J Cancer. 2010;46:439–48.CrossRefGoogle Scholar
  27. 27.
    Brinda BJ, Viganego F, Vo T, Dolan D, Fradley MG. Anti-VEGF-induced hypertension: a review of pathophysiology and treatment options. Curr Treat Options Cardiovasc Med. 2016;18:33.CrossRefGoogle Scholar
  28. 28.
    Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, et al. Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med. 2009;15:545–52.CrossRefGoogle Scholar
  29. 29.
    Steeghs N, Gelderblom H, Roodt JO, Christensen O, Rajagopalan P, Hovens M, et al. Hypertension and rarefaction during treatment with telatinib, a small molecule angiogenesis inhibitor. Clin Cancer Res. 2008;14:3470–6.CrossRefGoogle Scholar
  30. 30.
    Mourad JJ, des Guetz G, Debbabi H, Levy BI. Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol. 2008;19:927–34.CrossRefGoogle Scholar
  31. 31.
    Steeghs N, Rabelink TJ, op’t Roodt J, Batman E, Cluitmans FH, Weijl NI, et al. Reversibility of capillary density after discontinuation of bevacizumab treatment. Ann Oncol. 2010;21:1100–5.CrossRefGoogle Scholar
  32. 32.
    Hansen-Smith FM, Morris LW, Greene AS, Lombard JH. Rapid microvessel rarefaction with elevated salt intake and reduced renal mass hypertension in rats. Circ Res. 1996;79:324–30.CrossRefGoogle Scholar
  33. 33.
    Lindahl P, Johansson BR, Leveen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science. 1997;277:242–5.CrossRefGoogle Scholar
  34. 34.
    Vigneau C, Lorcy N, Dolley-Hitze T, Jouan F, Arlot-Bonnemains Y, Laguerre B, et al. All anti-vascular endothelial growth factor drugs can induce ‘pre-eclampsia-like syndrome’: a RARe study. Nephrol Dial Transplant. 2014;29:325–32.CrossRefGoogle Scholar
  35. 35.
    Amraoui F, Spijkers L, Hassani Lahsinoui H, Vogt L, van der Post J, Peters S, et al. SFlt-1 elevates blood pressure by augmenting endothelin-1-mediated vasoconstriction in mice. PLoS One. 2014;9(3):45.e91897.CrossRefGoogle Scholar
  36. 36.
    Eremina V, Jefferson JA, Kowalewska J, Hochster H, Haas M, Weisstuch J, et al. VEGF inhibition and renal thrombotic micro-angiopathy. N Engl J Med. 2008;358:1129–36.CrossRefGoogle Scholar
  37. 37.
    Izzedine H. Anti-VEGF cancer therapy in nephrology practice. Int J Nephrol Renov Dis. 2014;2014:143426.Google Scholar
  38. 38.
    DeJesus GN, Robinson E, Moslehi J, Humphreys BD. Management of antiangiogenic therapy-induced hypertension. Hypertension. 2012;60(3):607–15.CrossRefGoogle Scholar
  39. 39.
    Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst. 2011;103(9):763–73.CrossRefGoogle Scholar
  40. 40.
    Chen ZI, Ai DI. Cardiotoxicity associated with targeted cancer therapies. Mol Clin Oncol. 2016;4(5):675–81.CrossRefGoogle Scholar
  41. 41.
    Qi WX, Lin F, Sun YJ, Tang LN, He AN, Yao Y, et al. Incidence and risk of hypertension with pazopanib in patients with cancer: a meta-analysis. Cancer Chemother Pharmacol. 2013;71(2):431–9.CrossRefGoogle Scholar
  42. 42.
    Qi WX, He AN, Shen Z, Yao Y. Incidence and risk of hypertension with a novel multi-targeted kinase inhibitor axitinib in cancer patients: a systematic review and meta-analysis. Br J Clin Pharmacol. 2013;76:348–57.CrossRefGoogle Scholar
  43. 43.
    Cheng H, Force T. Molecular mechanisms of cardiovascular toxicity of targeted cancer therapeutics. Circ Res. 2010;106:21–34.CrossRefGoogle Scholar
  44. 44.
    Moslehi J, Minamishima YA, Shi J, Neuberg D, Charytan DM, Padera RF, et al. Loss of hypoxia-inducible factor prolyl hydroxylase activity in cardiomyocytes phenocopies ischemic cardiomyopathy. Circulation. 2010;122:1004–16.CrossRefGoogle Scholar
  45. 45.
    Chintalgattu V, Ai D, Langley RR, Zhang J, Bankson JA, Shih TL, et al. Cardiomyocyte PDGFR-beta signaling is an essential component of the mouse cardiac response to load-induced stress. J Clin Invest. 2010;120:472–84.CrossRefGoogle Scholar
  46. 46.
    Fazel S, Cimini M, Chen L, Li S, Angoulvant D, Fedak P, Verma S, et al. Cardioprotective c-kit± cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J Clin Invest. 2006;116:1865–77.CrossRefGoogle Scholar
  47. 47.
    Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, et al. Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest. 2005;115:2108–18.CrossRefGoogle Scholar
  48. 48.
    Pepe M, Mamdani M, Zentilin L, Csiszar A, Qanud K, Zacchigna S, et al. Intramyocardial VEGF-B167 gene delivery delays the progression towards congestive failure in dogs with pacing-induced dilated cardiomyopathy. Circ Res. 2010;106:1893–903.CrossRefGoogle Scholar
  49. 49.
    Kerkela R, Woulfe KC, Durand JB, Vagnozzi R, Kramer D, Chu TF, et al. Sunitinib-induced cardiotoxicity is mediated by off-target inhibition of AMP-activated protein kinase. Clin Transl Sci. 2009;2(1):15–25.CrossRefGoogle Scholar
  50. 50.
    Khakoo AY, Kassiotis CM, Tannir N, Plana JC, Halushka M, Bickford C, et al. Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. Cancer. 2008;112:2500–8.CrossRefGoogle Scholar
  51. 51.
    Totzeck M, Mincu RI, Rassaf T. Cardiovascular adverse events in patients with cancer treated with bevacizumab: a meta-analysis of more than 20,000 patients. J Am Heart Assoc. 2017;6(8):e006278.CrossRefGoogle Scholar
  52. 52.
    Hesser BA, Liang XH, Camenisch G, Yang S, Lewin DA, Scheller R, et al. Down syndrome critical region protein 1 (DSCR1), a novel VEGF target gene that regulates expression of inflammatory markers on activated endothelial cells. Blood. 2004;104(1):149–58.CrossRefGoogle Scholar
  53. 53.
    Kuenen BC, Levi M, Meijers JC, Kakkar AK, van Hinsbergh VW, Kostense PJ, et al. Analysis of coagulation cascade and endothelial cell activation during inhibition of vascular endothelial growth factor/vascular endothelial growth factor receptor pathway in cancer patients. Arterioscler Thromb Vasc Biol. 2002;22:1500–5.CrossRefGoogle Scholar
  54. 54.
    Hall PS, Harshman LC, Srinivas S, Witteles RM. The frequency and severity of cardiovascular toxicity from targeted therapy in advanced renal cell carcinoma patients. JACC Heart Fail. 2013;1:72–8.CrossRefGoogle Scholar
  55. 55.
    Economopoulou P, Kotsakis A, Kapiris I, Kentepozidis N. Cancer therapy and cardiovascular risk: focus on bevacizumab. Cancer Manag Res. 2015;7:133–43.CrossRefGoogle Scholar
  56. 56.
    Ranpura V, Hapani S, Chuang J, Wu S. Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials. Acta Oncol. 2010;49:287–97.CrossRefGoogle Scholar
  57. 57.
    Scappaticci FA, Skillings JR, Holden SN, Gerber HP, Miller K, Kabbinavar F, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99:1232–9.CrossRefGoogle Scholar
  58. 58.
    Choueiri TK, Schutz FA, Je Y, Rosenberg JE, Bellmunt J. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol. 2010;28(13):2280–5.CrossRefGoogle Scholar
  59. 59.
    Bronte G, Bronte E, Novo G, Pernice G, Lo Vullo F, Musso E, et al. Conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting tyrosine kinase inhibitor-based therapy. Expert Opin Drug Saf. 2015;14(2):253–67.CrossRefGoogle Scholar
  60. 60.
    Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061–8.CrossRefGoogle Scholar
  61. 61.
    Sarkiss MG, Yusuf SW, Warneke CL, Botz G, Lakkis N, Hirch-Ginsburg C, et al. Impact of aspirin therapy in cancer patients with thrombocytopenia and acute coronary syndromes. Cancer. 2007;109:621–7.CrossRefGoogle Scholar
  62. 62.
    Hurwitz HI, Saltz LB, Van Cutsem E, Cassidy J, Wiedemann J, Sirzén F, et al. Venous thromboembolic events with chemotherapy plus bevacizumab: a pooled analysis of patients in randomized phase II and III studies. J Clin Oncol. 2011;29:1757–64.CrossRefGoogle Scholar
  63. 63.
    Zamorano JL. Specific risk of atrial fibrillation and stroke in oncology patients. Eur Heart J. 2016;37(36):2747–8.CrossRefGoogle Scholar
  64. 64.
    Mandalà M, Falanga A, Roila F. ESMO Guidelines Working Group. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol. 2011;22(Suppl 6):vi85–92.PubMedGoogle Scholar
  65. 65.
    Zamorano J. An ESC position paper on cardio-oncology. Eur Heart J. 2016;37(36):2739–40.CrossRefGoogle Scholar
  66. 66.
    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;
  67. 67.
    Maitland ML, Bakris GL, Black HR, Chen HX, Durand JB, Elliott WJ, et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst. 2010;102:596–604.CrossRefGoogle Scholar
  68. 68.
    Vallerio P, Stucchi M, Moreo A, Ricotta R, Pozzi M, Giupponi L, et al. Possible role of arterial function in cancer treatment targeting vascular endothelial growth factor receptor oncologic response. J Hypertens. 2015;33(Suppl 1):e111.CrossRefGoogle Scholar
  69. 69.
    Moreo A, Vallerio P, Ricotta R, Stucchi M, Pozzi M, Musca F, et al. Effects of cancer therapy targeting vascular endothelial growth factor receptor on central blood pressure and cardiovascular system. Am J Hypertens. 2016;29:158–62.CrossRefGoogle Scholar
  70. 70.
    López-Fernández T, Martín García A, Santaballa Beltrán A, Montero Luis Á, García Sanz R, Mazón Ramos P, et al. Cardio-onco-hematology in clinical practice. Position paper and recommendations. Rev Esp Cardiol (Engl Ed). 2017;70(6):474–86.CrossRefGoogle Scholar
  71. 71.
    Zamorano JL, Lancellotti P, Rodriguez Muñoz D, Aboyans V, Asteggiano R, Galderisi M, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J. 2016;37(36):2768–801.CrossRefGoogle Scholar
  72. 72.
    Siddiqui AJ, Mansson-Broberg A, Gustafsson T, Grinnemo KH, Dellgren G, Hao X, et al. Antagonism of the renin-angiotensin system can counteract cardiac angiogenic vascular endothelial growth factor gene therapy and myocardial angiogenesis in the normal heart. Am J Hypertens. 2005;18:1347–52.CrossRefGoogle Scholar
  73. 73.
    Okwan-Duodu D, Landry J, Shen XZ, Diaz R. Angiotensin-converting enzyme and the tumor microenvironment: mechanisms beyond angiogenesis. Am J Physiol Regul Integr Comp Physiol. 2013;305:R205–15.CrossRefGoogle Scholar
  74. 74.
    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.CrossRefGoogle Scholar
  75. 75.
    Kruzliak P, Kovacova G, Pechanova O. Therapeutic potential of nitric oxide donors in the prevention and treatment of angiogenesis-inhibitor-induced hypertension. Angiogenesis. 2013;16:289–95.CrossRefGoogle Scholar
  76. 76.
    Okamoto LE, Gamboa A, Shibao CA, Arnold AC, Choi L, Black BK, et al. Nebivolol, but not metoprolol, lowers blood pressure in nitric oxide-sensitive human hypertension. Hypertension. 2014;64:1241–7.CrossRefGoogle Scholar
  77. 77.
    Dessy C, Saliez J, Ghisdal P, Daneau G, Lobysheva II, Frérart F, et al. Endothelial beta3-adrenoreceptors mediate nitric oxide-dependent vasorelaxation of coronary microvessels in response to the third-generation beta-blocker nebivolol. Circulation. 2005;112:1198–205.CrossRefGoogle Scholar
  78. 78.
    Dirix LY, Maes H, Sweldens C. Treatment of arterial hypertension (AHT) associated with angiogenesis inhibitors. Ann Oncol. 2007;18:1121–2.CrossRefGoogle Scholar
  79. 79.
    Maurea N, Spallarossa P, Cadeddu C, Madonna R, Mele D, Monte I, et al. A recommended practical approach to the management of target therapy and angiogenesis inhibitors cardiotoxicity: an opinion paper of the working group on drug cardiotoxicity and cardioprotection, Italian Society of Cardiology. J Cardiovasc Med (Hagerstown). 2016;17 Suppl 1 Special issue on Cardiotoxicity from Antiblastic Drugs and Cardioprotection:e93–104. Review.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Giuseppina Novo
    • 1
  • Daniela Di Lisi
    • 1
  • Enrico Bronte
    • 2
  • Manuela Fiuza
    • 3
  • Fausto J. Pinto
    • 3
  1. 1.Division of CardiologyBiomedical Department of Internal Medicine and Specialities (DIBIMIS), University of PalermoPalermoItaly
  2. 2.Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of PalermoPalermoItaly
  3. 3.Department of CardiologyUniversity Hospital Santa Maria, CHLN University of LisbonLisbonPortugal

Personalised recommendations