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  • Review Article
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Vascular toxic effects of cancer therapies

Nature Reviews Cardiology volume 17, pages 503–522 (2020)Cite this article

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Abstract

Cancer therapies can lead to a broad spectrum of cardiovascular complications. Among these, cardiotoxicities remain of prime concern, but vascular toxicities have emerged as the second most common group. The range of cancer therapies with a vascular toxicity profile and the clinical spectrum of vascular toxic effects are quite broad. Historically, venous thromboembolism has received the greatest attention but, over the past decade, the arterial toxic effects, which can present as acute vasospasm, acute thrombosis and accelerated atherosclerosis, of cancer therapies have gained greater recognition. This Review focuses on these types of cancer therapy-related arterial toxicity, including their mechanisms, and provides an update on venous thromboembolism and pulmonary hypertension associated with cancer therapies. Recommendations for the screening, treatment and prevention of vascular toxic effects of cancer therapies are outlined in the context of available evidence and society guidelines and consensus statements. The shift towards greater awareness of the vascular toxic effects of cancer therapies has further unveiled the urgent needs in this area in terms of defining best clinical practices. Well-designed and well-conducted clinical studies and registries are needed to more precisely define the incidence rates, risk factors, primary and secondary modes of prevention, and best treatment modalities for vascular toxicities related to cancer therapies. These efforts should be complemented by preclinical studies to outline the pathophysiological concepts that can be translated into the clinic and to identify drugs with vascular toxicity potential even before their widespread clinical use.

Key points

  • Vascular toxic effects of cancer therapies include arterial and venous events and affect the systemic and pulmonary circulations.

  • Cancer therapy-related arterial toxicities can present as acute vasospasm, acute thrombosis and accelerated atherosclerosis.

  • The management of cancer therapy-related vascular toxicities is directed towards the underlying pathological mechanism; therefore, defining the underlying mechanism is a central element.

  • The best modes of pre-therapy screening, surveillance and prevention are yet to be defined.

  • Clinical studies and registries are needed to define more precisely the risk, risk factors and risk management of the vascular toxic effects of cancer therapies.

  • Experimental studies should provide insight into the pathophysiological mechanisms of cardiovascular toxic effects of cancer therapies, which might also lead to an improved understanding of cardiovascular diseases in general.

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Fig. 1: Spectrum of vascular toxic effects of cancer therapies.
Fig. 2: Mechanisms of ischaemia in patients with cancer.
Fig. 3: Risk of arterial thromboembolic events in patients with cancer.
Fig. 4: Pathophysiological processes contributing to atherosclerosis in patients with cancer.

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References

  1. Herrmann, J. Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia. Nat. Rev. Cardiol. https://doi.org/10.1038/s41569-020-0348-1 (2020)

    Article  PubMed  Google Scholar 

  2. Kleiman, N. S., Lehane, D. E., Geyer, C. E. Jr., Pratt, C. M. & Young, J. B. Prinzmetal’s angina during 5-fluorouracil chemotherapy. Am. J. Med. 82, 566–568 (1987).

    CAS  PubMed  Google Scholar 

  3. Collins, C. & Weiden, P. L. Cardiotoxicity of 5-fluorouracil. Cancer Treat. Rep. 71, 733–736 (1987).

    CAS  PubMed  Google Scholar 

  4. Schnetzler, B., Popova, N., Collao Lamb, C. & Sappino, A. P. Coronary spasm induced by capecitabine. Ann. Oncol. 12, 723–724 (2001).

    CAS  PubMed  Google Scholar 

  5. Mosseri, M., Fingert, H. J., Varticovski, L., Chokshi, S. & Isner, J. M. In vitro evidence that myocardial ischemia resulting from 5-fluorouracil chemotherapy is due to protein kinase C-mediated vasoconstriction of vascular smooth muscle. Cancer Res. 53, 3028–3033 (1993).

    CAS  PubMed  Google Scholar 

  6. Lanza, G. A., Careri, G. & Crea, F. Mechanisms of coronary artery spasm. Circulation 124, 1774–1782 (2011).

    PubMed  Google Scholar 

  7. Cwikiel, M., Eskilsson, J., Wieslander, J. B., Stjernquist, U. & Albertsson, M. The appearance of endothelium in small arteries after treatment with 5-fluorouracil. An electron microscopic study of late effects in rabbits. Scanning Microsc. 10, 805–818; discussion 819 (1996).

    CAS  PubMed  Google Scholar 

  8. Herrmann, J. & Lerman, A. The endothelium: dysfunction and beyond. J. Nucl. Cardiol. 8, 197–206 (2001).

    CAS  PubMed  Google Scholar 

  9. Boyle, J. J. et al. Expression of angiogenic factor thymidine phosphorylase and angiogenesis in human atherosclerosis. J. Pathol. 192, 234–242 (2000).

    CAS  PubMed  Google Scholar 

  10. Meyer, C. C., Calis, K. A., Burke, L. B., Walawander, C. A. & Grasela, T. H. Symptomatic cardiotoxicity associated with 5-fluorouracil. Pharmacotherapy 17, 729–736 (1997).

    CAS  PubMed  Google Scholar 

  11. Saif, M. W., Shah, M. M. & Shah, A. R. Fluoropyrimidine-associated cardiotoxicity: revisited. Expert Opin. Drug Saf. 8, 191–202 (2009).

    CAS  PubMed  Google Scholar 

  12. Sara, J. D. et al. 5-fluorouracil and cardiotoxicity: a review. Ther. Adv. Med. Oncol. 10, 1758835918780140 (2018).

    PubMed  PubMed Central  Google Scholar 

  13. Gemici, G., Cincin, A., Degertekin, M. & Oktay, A. Paclitaxel-induced ST-segment elevations. Clin. Cardiol. 32, E94–E96 (2009).

    PubMed  PubMed Central  Google Scholar 

  14. Nguyen-Ho, P., Kleiman, N. S. & Verani, M. S. Acute myocardial infarction and cardiac arrest in a patient receiving paclitaxel. Can. J. Cardiol. 19, 300–302 (2003).

    PubMed  Google Scholar 

  15. Arbuck, S. G. et al. A reassessment of cardiac toxicity associated with Taxol. J. Natl. Cancer Inst. Monogr. 15, 117–130 (1993).

    Google Scholar 

  16. Shiroto, T. et al. Role of Rho-kinase in the pathogenesis of coronary hyperconstricting responses induced by drug-eluting stents in pigs in vivo. J. Am. Coll. Cardiol. 54, 2321–2329 (2009).

    CAS  PubMed  Google Scholar 

  17. Vassilakopoulou, M. et al. Paclitaxel chemotherapy and vascular toxicity as assessed by flow-mediated and nitrate-mediated vasodilatation. Vasc. Pharmacol. 53, 115–121 (2010).

    CAS  Google Scholar 

  18. Doll, D. C. et al. Acute vascular ischemic events after cisplatin-based combination chemotherapy for germ-cell tumors of the testis. Ann. Intern. Med. 105, 48–51 (1986).

    CAS  PubMed  Google Scholar 

  19. Taniguchi, T., Nakamura, T. & Sawada, T. Arterial stiffness, endothelial dysfunction and recurrent angina post-chemotherapy. QJM 108, 653–655 (2015).

    CAS  PubMed  Google Scholar 

  20. Stefenelli, T., Kuzmits, R., Ulrich, W. & Glogar, D. Acute vascular toxicity after combination chemotherapy with cisplatin, vinblastine, and bleomycin for testicular cancer. Eur. Heart J. 9, 552–556 (1988).

    CAS  PubMed  Google Scholar 

  21. Sekijima, T. et al. Impact of platinum-based chemotherapy on the progression of atherosclerosis. Climacteric 14, 31–40 (2011).

    CAS  PubMed  Google Scholar 

  22. Thijs, A. M. et al. Role of endogenous vascular endothelial growth factor in endothelium-dependent vasodilation in humans. Hypertension 61, 1060–1065 (2013).

    CAS  PubMed  Google Scholar 

  23. Thijs, A. M. et al. Impaired endothelium-dependent vasodilation does not initiate the development of sunitinib-associated hypertension. J. Hypertens. 33, 2075–2082 (2015).

    CAS  PubMed  Google Scholar 

  24. Touyz, R. M., Herrmann, S. M. S. & Herrmann, J. Vascular toxicities with VEGF inhibitor therapies-focus on hypertension and arterial thrombotic events. J. Am. Soc. Hypertens. 12, 409–425 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Kappers, M. H. et al. Sunitinib-induced systemic vasoconstriction in swine is endothelin mediated and does not involve nitric oxide or oxidative stress. Hypertension 59, 151–157 (2012).

    CAS  Google Scholar 

  26. Kappers, M. H. et al. Hypertension induced by the tyrosine kinase inhibitor sunitinib is associated with increased circulating endothelin-1 levels. Hypertension 56, 675–681 (2010).

    CAS  Google Scholar 

  27. Sen, F. et al. Impaired coronary flow reserve in metastatic cancer patients treated with sunitinib. J. BUON 18, 775–781 (2013).

    CAS  PubMed  Google Scholar 

  28. Reimann, M. et al. Anti-vascular endothelial growth factor therapy impairs endothelial function of retinal microcirculation in colon cancer patients – an observational study. Exp. Transl. Stroke Med. 5, 7 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Katoh, M. et al. Bevacizumab-related microvascular angina and its management with Nicorandil. Int. Heart J. 58, 803–805 (2017).

    PubMed  Google Scholar 

  30. Arima, Y. et al. Sorafenib-induced acute myocardial infarction due to coronary artery spasm. J. Cardiol. 54, 512–515 (2009).

    PubMed  Google Scholar 

  31. Naib, T., Steingart, R. M. & Chen, C. L. Sorafenib-associated multivessel coronary artery vasospasm. Herz 36, 348–351 (2011).

    CAS  PubMed  Google Scholar 

  32. Hingorani, A. D. et al. Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation 102, 994–999 (2000).

    CAS  PubMed  Google Scholar 

  33. Pleiner, J. et al. Simvastatin prevents vascular hyporeactivity during inflammation. Circulation 110, 3349–3354 (2004).

    CAS  PubMed  Google Scholar 

  34. Levy, B. et al. Vascular hyporesponsiveness to vasopressors in septic shock: from bench to bedside. Intensive Care Med. 36, 2019–2029 (2010).

    CAS  PubMed  Google Scholar 

  35. Miller, D. D., Waters, D. D., Dangoisse, V. & David, P. R. Symptomatic coronary artery spasm following radiotherapy for Hodgkin’s disease. Chest 83, 284–285 (1983).

    CAS  PubMed  Google Scholar 

  36. Yahalom, J., Hasin, Y. & Fuks, Z. Acute myocardial infarction with normal coronary arteriogram after mantle field radiation therapy for Hodgkin’s disease. Cancer 52, 637–641 (1983).

    CAS  PubMed  Google Scholar 

  37. Egashira, S. et al. Mechanisms of ergonovine-induced hyperconstriction of coronary artery after x-ray irradiation in pigs. Basic Res. Cardiol. 90, 167–175 (1995).

    CAS  PubMed  Google Scholar 

  38. Soloviev, A. I. et al. Mechanisms of endothelial dysfunction after ionized radiation: selective impairment of the nitric oxide component of endothelium-dependent vasodilation. Br. J. Pharmacol. 138, 837–844 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Sugihara, T. et al. Preferential impairment of nitric oxide-mediated endothelium-dependent relaxation in human cervical arteries after irradiation. Circulation 100, 635–641 (1999).

    CAS  PubMed  Google Scholar 

  40. Beckman, J. A., Thakore, A., Kalinowski, B. H., Harris, J. R. & Creager, M. A. Radiation therapy impairs endothelium-dependent vasodilation in humans. J. Am. Coll. Cardiol. 37, 761–765 (2001).

    CAS  PubMed  Google Scholar 

  41. Levesque, L. et al. Effects of radiation therapy on vascular responsiveness. J. Cardiovasc. Pharmacol. 37, 381–393 (2001).

    CAS  PubMed  Google Scholar 

  42. Centola, M. et al. A rare case of large intracoronary thrombosis in advanced breast cancer patient treated with epirubicin and cisplatin. J. Cardiovasc. Med. 17 (Suppl. 2), e241–e243 (2016).

    Google Scholar 

  43. Ito, D. et al. Primary percutaneous coronary intervention and intravascular ultrasound imaging for coronary thrombosis after cisplatin-based chemotherapy. Heart Vessels 27, 634–638 (2012).

    PubMed  Google Scholar 

  44. Jafri, M. & Protheroe, A. Cisplatin-associated thrombosis. Anticancer Drugs 19, 927–929 (2008).

    CAS  PubMed  Google Scholar 

  45. Karabay, K. O., Yildiz, O. & Aytekin, V. Multiple coronary thrombi with cisplatin. J. Invasive Cardiol. 26, E18–E20 (2014).

    PubMed  Google Scholar 

  46. Karavelioglu, Y., Ekicibasi, E., Tanalp, A. C., Karapinar, H. & Aung, S. M. Worm-like thrombus in left main coronary artery after cytostatic treatment. Blood Coagul. Fibrinolysis 21, 491–493 (2010).

    PubMed  Google Scholar 

  47. Morlese, J. F., Jeswani, T., Beal, I., Wylie, P. & Bell, J. Acute ventricular and aortic thrombosis post chemotherapy. Br. J. Radiol. 80, e75–e77 (2007).

    CAS  PubMed  Google Scholar 

  48. Pretnar-Oblak, J., Zaletel, M., Jagodic, M. & Zaletel, M. Thrombosis of internal carotid artery after cisplatin-based chemotherapy. Eur. Neurol. 57, 109–110 (2007).

    PubMed  Google Scholar 

  49. Rishi, A. & Ghoshal, S. Acute multiple arterial thrombosis after cisplatin in base of tongue carcinoma: case report. Head Neck 35, E269–E271 (2013).

    PubMed  Google Scholar 

  50. Kawano, N. et al. Two cases of acute myocardial infarction during combined chemotherapy in young patients with testicular cancer. J. Cardiol. Cases 7, e176–e180 (2013).

    PubMed  PubMed Central  Google Scholar 

  51. Ozkan, T. A., Aydin, U., Ay, D. & Cebeci, I. O. Cisplatin and bleomycin-induced acute peripheral-vascular stenosis in patient with testicular cancer. Urol. Ann. 8, 483–485 (2016).

    PubMed  PubMed Central  Google Scholar 

  52. Moore, R. A. et al. High incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis. J. Clin. Oncol. 29, 3466–3473 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Crea, F. & Libby, P. Acute coronary syndromes: the way forward from mechanisms to precision treatment. Circulation 136, 1155–1166 (2017).

    PubMed  PubMed Central  Google Scholar 

  54. Partida, R. A., Libby, P., Crea, F. & Jang, I. K. Plaque erosion: a new in vivo diagnosis and a potential major shift in the management of patients with acute coronary syndromes. Eur. Heart J. 39, 2070–2076 (2018).

    PubMed  PubMed Central  Google Scholar 

  55. Quillard, T. et al. TLR2 and neutrophils potentiate endothelial stress, apoptosis and detachment: implications for superficial erosion. Eur. Heart J. 36, 1394–1404 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Libby, P., Pasterkamp, G., Crea, F. & Jang, I. K. Reassessing the mechanisms of acute coronary syndromes. Circ. Res. 124, 150–160 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Folco, E. J. et al. Neutrophil extracellular traps induce endothelial cell activation and tissue factor production through interleukin-1α and cathepsin G. Arterioscler. Thromb. Vasc. Biol. 38, 1901–1912 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Franck, G. et al. Flow perturbation mediates neutrophil recruitment and potentiates endothelial injury via TLR2 in mice: implications for superficial erosion. Circ. Res. 121, 31–42 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Libby, P. & Croce, K. Visualizing the vascular glue “shearing” the barriers to atherosclerotic plaque imaging. JACC Cardiovasc. Imaging 3, 956–958 (2010).

    PubMed  Google Scholar 

  60. Hagensen, M. K. et al. Circulating endothelial progenitor cells do not contribute to regeneration of endothelium after murine arterial injury. Cardiovasc. Res. 93, 223–231 (2012).

    CAS  PubMed  Google Scholar 

  61. Padfield, G. J., Newby, D. E. & Mills, N. L. Understanding the role of endothelial progenitor cells in percutaneous coronary intervention. J. Am. Coll. Cardiol. 55, 1553–1565 (2010).

    PubMed  Google Scholar 

  62. Douglas, G. et al. Endothelial cell repopulation after stenting determines in-stent neointima formation: effects of bare-metal vs. drug-eluting stents and genetic endothelial cell modification. Eur. Heart J. 34, 3378–3388 (2013).

    CAS  PubMed  Google Scholar 

  63. Ramcharan, K. S., Lip, G. Y., Stonelake, P. S. & Blann, A. D. Effect of standard chemotherapy and antiangiogenic therapy on plasma markers and endothelial cells in colorectal cancer. Br. J. Cancer 111, 1742–1749 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Oren, O. & Herrmann, J. Arterial events in cancer patients-the case of acute coronary thrombosis. J. Thorac. Dis. 10, S4367–S4385 (2018).

    PubMed  PubMed Central  Google Scholar 

  65. Bauer, A. T. et al. von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans. Blood 125, 3153–3163 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Yang, A. J. et al. Cancer cell-derived von Willebrand factor enhanced metastasis of gastric adenocarcinoma. Oncogenesis 7, 12 (2018).

    PubMed  PubMed Central  Google Scholar 

  67. Navi, B. B. et al. Risk of arterial thromboembolism in patients with cancer. J. Am. Coll. Cardiol. 70, 926–938 (2017).

    PubMed  PubMed Central  Google Scholar 

  68. Timp, J. F., Braekkan, S. K., Versteeg, H. H. & Cannegieter, S. C. Epidemiology of cancer-associated venous thrombosis. Blood 122, 1712–1723 (2013).

    CAS  PubMed  Google Scholar 

  69. Chew, H. K., Wun, T., Harvey, D., Zhou, H. & White, R. H. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch. Intern. Med. 166, 458–464 (2006).

    PubMed  Google Scholar 

  70. Blann, A. D. & Dunmore, S. Arterial and venous thrombosis in cancer patients. Cardiol. Res. Pract. 2011, 394740 (2011).

    PubMed  PubMed Central  Google Scholar 

  71. Dieckmann, K. P., Struss, W. J. & Budde, U. Evidence for acute vascular toxicity of cisplatin-based chemotherapy in patients with germ cell tumour. Anticancer Res. 31, 4501–4505 (2011).

    CAS  PubMed  Google Scholar 

  72. Patel, J. N. et al. Bevacizumab and the risk of arterial and venous thromboembolism in patients with metastatic, castration-resistant prostate cancer treated on Cancer and Leukemia Group B (CALGB) 90401 (Alliance). Cancer 121, 1025–1031 (2015).

    CAS  PubMed  Google Scholar 

  73. Suzuki, K., Yanagimura, T., Ohashi, K., Kagamu, H. & Takada, T. Bevacizumab-induced aortic arterial thrombosis. Intern. Med. 57, 2987–2990 (2018).

    PubMed  PubMed Central  Google Scholar 

  74. Lamba, G., Deol, R., Shah, D., Sahni, R. & Malhotra, B. K. Sunitinib and thrombosis. J. Gastrointest. Cancer 43 (Suppl. 1), S128–S130 (2012).

    PubMed  Google Scholar 

  75. Grieco, A., Lombardo, A. & Biolato, M. Ventricular thrombosis during sorafenib therapy for advanced hepatocellular carcinoma. Eur. J. Gastroenterol. Hepatol. 25, 1001–1002 (2013).

    PubMed  Google Scholar 

  76. Meyer, T. et al. Bevacizumab immune complexes activate platelets and induce thrombosis in FCGR2A transgenic mice. J. Thromb. Haemost. 7, 171–181 (2009).

    CAS  PubMed  Google Scholar 

  77. Chen, N. et al. Bevacizumab promotes venous thromboembolism through the induction of PAI-1 in a mouse xenograft model of human lung carcinoma. Mol. Cancer 14, 140 (2015).

    PubMed  PubMed Central  Google Scholar 

  78. Kilickap, S., Abali, H. & Celik, I. Bevacizumab, bleeding, thrombosis, and warfarin. J. Clin. Oncol. 21, 3542 (2003).

    PubMed  Google Scholar 

  79. Sabrkhany, S. et al. Sunitinib uptake inhibits platelet function in cancer patients. Eur. J. Cancer 66, 47–54 (2016).

    CAS  PubMed  Google Scholar 

  80. Walraven, M. et al. Platelet function is disturbed by the angiogenesis inhibitors sunitinib and sorafenib, but unaffected by bevacizumab. Angiogenesis 21, 325–334 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Herrmann, J. Tyrosine kinase inhibitors and vascular toxicity: impetus for a classification system? Curr. Oncol. Rep. 18, 33 (2016).

    PubMed  Google Scholar 

  82. Gratacap, M. P. et al. The new tyrosine-kinase inhibitor and anticancer drug dasatinib reversibly affects platelet activation in vitro and in vivo. Blood 114, 1884–1892 (2009).

    CAS  PubMed  Google Scholar 

  83. Quintas-Cardama, A., Han, X., Kantarjian, H. & Cortes, J. Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia. Blood 114, 261–263 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Alhawiti, N. et al. The tyrosine kinase inhibitor, nilotinib potentiates a prothrombotic state. Thromb. Res. 145, 54–64 (2016).

    CAS  PubMed  Google Scholar 

  85. Loren, C. P. et al. The BCR-ABL inhibitor ponatinib inhibits platelet immunoreceptor tyrosine-based activation motif (ITAM) signaling, platelet activation and aggregate formation under shear. Thromb. Res. 135, 155–160 (2015).

    CAS  PubMed  Google Scholar 

  86. Neelakantan, P. et al. Platelet dysfunction associated with ponatinib, a new pan BCR-ABL inhibitor with efficacy for chronic myeloid leukemia resistant to multiple tyrosine kinase inhibitor therapy. Haematologica 97, 1444 (2012).

    PubMed  PubMed Central  Google Scholar 

  87. Tsukamoto, J. et al. Thromboembolic events related to treatment with checkpoint inhibitors: report of two cases. Case Rep. Oncol. 11, 648–653 (2018).

    PubMed  PubMed Central  Google Scholar 

  88. Kunimasa, K. et al. Pembrolizumab-induced acute thrombosis: a case report. Medicine 97, e10772 (2018).

    PubMed  PubMed Central  Google Scholar 

  89. Boutros, C. et al. Arterial thrombosis and anti-PD-1 blockade. Eur. J. Cancer 91, 164–166 (2018).

    PubMed  Google Scholar 

  90. Lipinska-Gediga, M. Coagulopathy in sepsis – a new look at an old problem. Anaesthesiol. Intensive Ther. 48, 352–359 (2016).

    PubMed  Google Scholar 

  91. Budnik, I. & Brill, A. Immune factors in deep vein thrombosis initiation. Trends Immunol. 39, 610–623 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Branchford, B. R. & Carpenter, S. L. The role of inflammation in venous thromboembolism. Front. Pediatr. 6, 142 (2018).

    PubMed  PubMed Central  Google Scholar 

  93. Bockmeyer, C. L. et al. Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor. Haematologica 93, 137–140 (2008).

    CAS  PubMed  Google Scholar 

  94. Higgins, J. N., Wlodarczyk, Z., Platts, A. D. & Hamilton, G. Radiation-induced acute femoral artery thrombosis treated by thrombolysis. Br. J. Surg. 79, 909–910 (1992).

    CAS  PubMed  Google Scholar 

  95. Reed, R. & Sadiq, S. Acute carotid artery thrombosis after neck irradiation. J. Ultrasound Med. 13, 641–644 (1994).

    CAS  PubMed  Google Scholar 

  96. Fonkalsrud, E. W., Sanchez, M., Zerubavel, R. & Mahoney, A. Serial changes in arterial structure following radiation therapy. Surg. Gynecol. Obstet. 145, 395–400 (1977).

    CAS  PubMed  Google Scholar 

  97. Schmidt-Lucke, C. et al. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation 111, 2981–2987 (2005).

    PubMed  Google Scholar 

  98. Vasa, M. et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ. Res. 89, E1–7 (2001).

    CAS  PubMed  Google Scholar 

  99. Iliescu, C. A. et al. SCAI Expert Consensus Statement: evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (endorsed by the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia Intervencionista). Catheter. Cardiovasc. Interv. 87, E202–E223 (2016).

    PubMed  Google Scholar 

  100. Neumann, F. J. et al. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur. Heart J. 40, 87–165 (2019).

    PubMed  Google Scholar 

  101. Gogas, B. D., McDaniel, M., Samady, H. & King, S. B. III. Novel drug-eluting stents for coronary revascularization. Trends Cardiovasc. Med. 24, 305–313 (2014).

    CAS  PubMed  Google Scholar 

  102. Urban, P. et al. Polymer-free drug-coated coronary stents in patients at high bleeding risk. N. Engl. J. Med. 373, 2038–2047 (2015).

    CAS  PubMed  Google Scholar 

  103. Palmerini, T. et al. Stent thrombosis with drug-eluting and bare-metal stents: evidence from a comprehensive network meta-analysis. Lancet 379, 1393–1402 (2012).

    CAS  PubMed  Google Scholar 

  104. Smith, S. C., Winters, K. J. & Lasala, J. M. Stent thrombosis in a patient receiving chemotherapy. Cathet. Cardiovasc. Diagn. 40, 383–386 (1997).

    CAS  PubMed  Google Scholar 

  105. Yeh, R. W. et al. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 315, 1735–1749 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Costa, F. et al. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet 389, 1025–1034 (2017).

    PubMed  Google Scholar 

  107. Gori, T. et al. Predictors of stent thrombosis and their implications for clinical practice. Nat. Rev. Cardiol. 16, 243–256 (2019).

    PubMed  Google Scholar 

  108. Iliescu, C. et al. SCAI Expert Consensus Statement: evaluation, management, and special considerations of cardio-oncology patients in the cardiac catheterization laboratory (endorsed by the Cardiological Society of India, and Sociedad Latino Americana de Cardiologia Intervencionista). Catheter. Cardiovasc. Interv. 87, 895–899 (2016).

    PubMed  Google Scholar 

  109. Thygesen, K. et al. Fourth universal definition of myocardial infarction (2018). J. Am. Coll. Cardiol. 72, 2231–2264 (2018).

    PubMed  Google Scholar 

  110. Park, J. Y. et al. Acute coronary syndromes in patients with active hematologic malignancies - Incidence, management, and outcomes. Int. J. Cardiol. 275, 6–12 (2019).

    PubMed  Google Scholar 

  111. McCarthy, C. P., Vaduganathan, M. & Januzzi, J. L. Jr. Type 2 myocardial infarction-diagnosis, prognosis, and treatment. JAMA 320, 433–434 (2018).

    PubMed  Google Scholar 

  112. Scappaticci, F. A. et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J. Natl Cancer Inst. 99, 1232–1239 (2007).

    PubMed  Google Scholar 

  113. Lee, S. et al. Autocrine VEGF signaling is required for vascular homeostasis. Cell 130, 691–703 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Lubberts, S. et al. Vascular fingerprint and vascular damage markers associated with vascular events in testicular cancer patients during and after chemotherapy. Eur. J. Cancer 63, 180–188 (2016).

    CAS  PubMed  Google Scholar 

  115. Soultati, A. et al. Endothelial vascular toxicity from chemotherapeutic agents: preclinical evidence and clinical implications. Cancer Treat. Rev. 38, 473–483 (2012).

    CAS  PubMed  Google Scholar 

  116. Jang, W. J., Choi, D. Y. & Jeon, I. S. Vascular endothelial dysfunction after anthracyclines treatment in children with acute lymphoblastic leukemia. Korean J. Pediatr. 56, 130–134 (2013).

    PubMed  PubMed Central  Google Scholar 

  117. Drafts, B. C. et al. Low to moderate dose anthracycline-based chemotherapy is associated with early noninvasive imaging evidence of subclinical cardiovascular disease. JACC Cardiovasc. Imaging 6, 877–885 (2013).

    PubMed  PubMed Central  Google Scholar 

  118. Vaughn, D. J., Palmer, S. C., Carver, J. R., Jacobs, L. A. & Mohler, E. R. Cardiovascular risk in long-term survivors of testicular cancer. Cancer 112, 1949–1953 (2008).

    PubMed  Google Scholar 

  119. Gietema, J. A. et al. Circulating plasma platinum more than 10 years after cisplatin treatment for testicular cancer. Lancet 355, 1075–1076 (2000).

    CAS  PubMed  Google Scholar 

  120. Meinardi, M. T. et al. Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J. Clin. Oncol. 18, 1725–1732 (2000).

    CAS  PubMed  Google Scholar 

  121. van den Belt-Dusebout, A. W. et al. Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J. Clin. Oncol. 24, 467–475 (2006).

    PubMed  Google Scholar 

  122. van den Belt-Dusebout, A. W. et al. Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J. Clin. Oncol. 25, 4370–4378 (2007).

    PubMed  Google Scholar 

  123. Haugnes, H. S. et al. Cardiovascular risk factors and morbidity in long-term survivors of testicular cancer: a 20-year follow-up study. J. Clin. Oncol. 28, 4649–4657 (2010).

    PubMed  Google Scholar 

  124. Huddart, R. A. et al. Cardiovascular disease as a long-term complication of treatment for testicular cancer. J. Clin. Oncol. 21, 1513–1523 (2003).

    CAS  PubMed  Google Scholar 

  125. Gugic, J., Zaletel, L. Z. & Oblak, I. Treatment-related cardiovascular toxicity in long-term survivors of testicular cancer. Radiol. Oncol. 51, 221–227 (2017).

    CAS  PubMed  Google Scholar 

  126. Haugnes, H. S., Oldenburg, J. & Bremnes, R. M. Pulmonary and cardiovascular toxicity in long-term testicular cancer survivors. Urol. Oncol. 33, 399–406 (2015).

    PubMed  Google Scholar 

  127. Bokemeyer, C., Berger, C. C., Kuczyk, M. A. & Schmoll, H. J. Evaluation of long-term toxicity after chemotherapy for testicular cancer. J. Clin. Oncol. 14, 2923–2932 (1996).

    CAS  PubMed  Google Scholar 

  128. Ishioka, J. et al. Cardiovascular events in survivors of high-dose chemotherapy for germ cell tumors. Int. J. Urol. 15, 642–645 (2008).

    CAS  PubMed  Google Scholar 

  129. Haugnes, H. S. et al. Predicted cardiovascular mortality and reported cardiovascular morbidity in testicular cancer survivors. J. Cancer Surviv. 2, 128–137 (2008).

    CAS  PubMed  Google Scholar 

  130. Gietema, J. A. et al. Long-term follow-up of cardiovascular risk factors in patients given chemotherapy for disseminated nonseminomatous testicular cancer. Ann. Intern. Med. 116, 709–715 (1992).

    CAS  PubMed  Google Scholar 

  131. Koc, G., Divrik, T. R., Unlu, N., Bulut, V. & Zorlu, F. Does cisplatin-based chemotherapy effect on blood lipid levels of patients with germ cell testicular tumor in long-term follow-up? Int. Urol. Nephrol. 43, 1095–1100 (2011).

    CAS  PubMed  Google Scholar 

  132. Levine, G. N. et al. Androgen-deprivation therapy in prostate cancer and cardiovascular risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: endorsed by the American Society for Radiation Oncology. Circulation 121, 833–840 (2010).

    PubMed  PubMed Central  Google Scholar 

  133. Bosco, C. et al. Quantifying observational evidence for risk of fatal and nonfatal cardiovascular disease following androgen deprivation therapy for prostate cancer: a meta-analysis. Eur. Urol. 68, 386–396 (2015).

    PubMed  Google Scholar 

  134. Keating, N. L. Type of androgen deprivation therapy and risk of cardiovascular disease. Eur. Urol. 72, 929–930 (2017).

    PubMed  Google Scholar 

  135. Winnik, S. et al. Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis – implications for cardiovascular safety. Int. J. Cardiol. 168, 2453–2461 (2013).

    PubMed  Google Scholar 

  136. Herrmann, J., Lerman, L. O., Mukhopadhyay, D., Napoli, C. & Lerman, A. Angiogenesis in atherogenesis. Arterioscler. Thromb. Vasc. Biol. 26, 1948–1957 (2006).

    CAS  PubMed  Google Scholar 

  137. Celletti, F. L. et al. Vascular endothelial growth factor enhances atherosclerotic plaque progression. Nat. Med. 7, 425–429 (2001).

    CAS  PubMed  Google Scholar 

  138. Zhao, Q. et al. Vascular endothelial growth factor is necessary in the development of arteriosclerosis by recruiting/activating monocytes in a rat model of long-term inhibition of nitric oxide synthesis. Circulation 105, 1110–1115 (2002).

    CAS  PubMed  Google Scholar 

  139. Lemstrom, K. B. et al. Vascular endothelial growth factor enhances cardiac allograft arteriosclerosis. Circulation 105, 2524–2530 (2002).

    CAS  PubMed  Google Scholar 

  140. Moulton, K. S. et al. Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation 99, 1726–1732 (1999).

    CAS  PubMed  Google Scholar 

  141. Moulton, K. S. et al. Inhibition of plaque neovascularization reduces macrophage accumulation and progression of advanced atherosclerosis. Proc. Natl Acad. Sci. USA 100, 4736–4741 (2003).

    CAS  PubMed  Google Scholar 

  142. Aichberger, K. J. et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in CML. Am. J. Hematol. 86, 533–539 (2011).

    CAS  PubMed  Google Scholar 

  143. Le Coutre, P. et al. Severe peripheral arterial disease during nilotinib therapy. J. Natl Cancer Inst. 103, 1347–1348 (2011).

    PubMed  Google Scholar 

  144. Tefferi, A. & Letendre, L. Nilotinib treatment-associated peripheral artery disease and sudden death: yet another reason to stick to imatinib as front-line therapy for chronic myelogenous leukemia. Am. J. Hematol. 86, 610–611 (2011).

    PubMed  Google Scholar 

  145. Breccia, M., Efficace, F. & Alimena, G. Progressive arterial occlusive disease (PAOD) and pulmonary arterial hypertension (PAH) as new adverse events of second generation TKIs in CML treatment: who’s afraid of the big bad wolf? Leuk. Res. 36, 813–814 (2012).

    PubMed  Google Scholar 

  146. Giles, F. J. et al. Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis. Leukemia 27, 1310–1315 (2013).

    CAS  PubMed  Google Scholar 

  147. Kim, T. D. et al. Peripheral artery occlusive disease in chronic phase chronic myeloid leukemia patients treated with nilotinib or imatinib. Leukemia 27, 1316–1321 (2013).

    CAS  PubMed  Google Scholar 

  148. Levato, L. et al. Progressive peripheral arterial occlusive disease and other vascular events during nilotinib therapy in chronic myeloid leukemia: a single institution study. Eur. J. Haematol. 90, 531–532 (2013).

    CAS  PubMed  Google Scholar 

  149. Tefferi, A. Nilotinib treatment-associated accelerated atherosclerosis: when is the risk justified? Leukemia 27, 1939–1940 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Maurizot, A. et al. Rapid clinical improvement of peripheral artery occlusive disease symptoms after nilotinib discontinuation despite persisting vascular occlusion. Blood Cancer J. 4, e247 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Breccia, M., Molica, M., Zacheo, I., Serrao, A. & Alimena, G. Application of systematic coronary risk evaluation chart to identify chronic myeloid leukemia patients at risk of cardiovascular diseases during nilotinib treatment. Ann. Hematol. 94, 393–397 (2015).

    CAS  PubMed  Google Scholar 

  152. Mirault, T., Rea, D., Azarine, A. & Messas, E. Rapid onset of peripheral artery disease in a chronic myeloid leukemia patient without prior arterial disorder: direct relationship with nilotinib exposure and clinical outcome. Eur. J. Haematol. 94, 363–367 (2015).

    CAS  PubMed  Google Scholar 

  153. Valent, P. et al. Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors. Blood 125, 901–906 (2015).

    CAS  PubMed  Google Scholar 

  154. Herrmann, J. et al. Complicated and advanced atherosclerosis in a young woman with Philadelphia chromosome-positive acute lymphoblastic leukemia: success and challenges of BCR/ABL1-targeted cancer therapy. Mayo Clin. Proc. 90, 1167–1168 (2015).

    PubMed  Google Scholar 

  155. Chai-Adisaksopha, C., Lam, W. & Hillis, C. Major arterial events in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a meta-analysis. Leuk. Lymphoma 57, 1300–1310 (2016).

    CAS  PubMed  Google Scholar 

  156. Douxfils, J. et al. Association between BCR-ABL tyrosine kinase inhibitors for chronic myeloid leukemia and cardiovascular events, major molecular response, and overall survival: a systematic review and meta-analysis. JAMA Oncol. 2, 625–632 (2016).

    PubMed  Google Scholar 

  157. Dahlen, T. et al. Cardiovascular events associated with use of tyrosine kinase inhibitors in chronic myeloid leukemia: a population-based cohort study. Ann. Intern. Med. 165, 161–166 (2016).

    PubMed  Google Scholar 

  158. Gover-Proaktor, A. et al. Bosutinib, dasatinib, imatinib, nilotinib, and ponatinib differentially affect the vascular molecular pathways and functionality of human endothelial cells. Leuk. Lymphoma 60, 189–199 (2019).

    CAS  PubMed  Google Scholar 

  159. Hadzijusufovic, E. et al. Nilotinib-induced vasculopathy: identification of vascular endothelial cells as a primary target site. Leukemia 31, 2388–2397 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  160. Gover-Proaktor, A. et al. Ponatinib reduces viability, migration, and functionality of human endothelial cells. Leuk. Lymphoma 58, 1455–1467 (2017).

    CAS  PubMed  Google Scholar 

  161. Pouwer, M. G. et al. The BCR-ABL1 inhibitors imatinib and ponatinib decrease plasma cholesterol and atherosclerosis, and nilotinib and ponatinib activate coagulation in a translational mouse model. Front. Cardiovasc. Med. 5, 55 (2018).

    PubMed  PubMed Central  Google Scholar 

  162. Bocchia, M. et al. Genetic predisposition and induced pro-inflammatory/pro-oxidative status may play a role in increased atherothrombotic events in nilotinib treated chronic myeloid leukemia patients. Oncotarget 7, 72311–72321 (2016).

    PubMed  PubMed Central  Google Scholar 

  163. Breccia, M. et al. Proposal for a tailored stratification at baseline and monitoring of cardiovascular effects during follow-up in chronic phase chronic myeloid leukemia patients treated with nilotinib frontline. Crit. Rev. Oncol. Hematol. 107, 190–198 (2016).

    PubMed  Google Scholar 

  164. Aghel, N., Lipton, J. H., Atenafu, E. G., Kim, D. D. H. & Delgado, D. H. Cardiovascular events after exposure to nilotinib in chronic myeloid leukemia: long-term follow-up. Clin. Lymphoma Myeloma Leuk. 17, 870–878.e1 (2017).

    PubMed  Google Scholar 

  165. Fujioka, I. et al. Features of vascular adverse events in Japanese patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a retrospective study of the CML cooperative study group database. Ann. Hematol. 97, 2081–2088 (2018).

    CAS  PubMed  Google Scholar 

  166. Fuster, J. J. & Walsh, K. Somatic mutations and clonal hematopoiesis: unexpected potential new drivers of age-related cardiovascular disease. Circ. Res. 122, 523–532 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Natarajan, P., Jaiswal, S. & Kathiresan, S. Clonal hematopoiesis: somatic mutations in blood cells and atherosclerosis. Circ. Genom. Precis. Med. 11, e001926 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Ebert, B. L. & Libby, P. Clonal hematopoiesis confers predisposition to both cardiovascular disease and cancer: a newly recognized link between two major killers. Ann. Intern. Med. 169, 116–117 (2018).

    PubMed  Google Scholar 

  169. Jaiswal, S. et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N. Engl. J. Med. 377, 111–121 (2017).

    PubMed  PubMed Central  Google Scholar 

  170. Cimmino, L. et al. Restoration of TET2 function blocks aberrant self-renewal and leukemia progression. Cell 170, 1079–1095.e20 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Fuster, J. J. et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842–847 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    CAS  PubMed  Google Scholar 

  173. Ridker, P. M. et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet 390, 1833–1842 (2017).

    CAS  PubMed  Google Scholar 

  174. Brunner, A. M. et al. Risk and timing of cardiovascular death among patients with myelodysplastic syndromes. Blood Adv. 1, 2032–2040 (2017).

    PubMed  PubMed Central  Google Scholar 

  175. Carobbio, A. et al. Risk factors for arterial and venous thrombosis in WHO-defined essential thrombocythemia: an international study of 891 patients. Blood 117, 5857–5859 (2011).

    CAS  PubMed  Google Scholar 

  176. Cucuianu, A. et al. Arterial stenosis and atherothrombotic events in polycythemia vera and essential thrombocythemia. Rom. J. Intern. Med. 44, 397–406 (2006).

    CAS  PubMed  Google Scholar 

  177. Vianello, F. et al. Coronary microvascular dysfunction due to essential thrombocythemia and policythemia vera: the missing piece in the puzzle of their increased cardiovascular risk? Am. J. Hematol. 90, 109–113 (2015).

    PubMed  Google Scholar 

  178. Maslah, N., Cassinat, B., Verger, E., Kiladjian, J. J. & Velazquez, L. The role of LNK/SH2B3 genetic alterations in myeloproliferative neoplasms and other hematological disorders. Leukemia 31, 1661–1670 (2017).

    CAS  PubMed  Google Scholar 

  179. Wang, W. et al. LNK/SH2B3 loss of function promotes atherosclerosis and thrombosis. Circ. Res. 119, e91–e103 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Swirski, F. K. & Nahrendorf, M. Bone marrow takes center stage in cardiovascular disease. Circ. Res. 119, 701–703 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Hanoun, M., Maryanovich, M., Arnal-Estape, A. & Frenette, P. S. Neural regulation of hematopoiesis, inflammation, and cancer. Neuron 86, 360–373 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Seijkens, T. et al. Hypercholesterolemia-induced priming of hematopoietic stem and progenitor cells aggravates atherosclerosis. FASEB J. 28, 2202–2213 (2014).

    CAS  PubMed  Google Scholar 

  183. Dutta, P. et al. Myocardial infarction accelerates atherosclerosis. Nature 487, 325–329 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  184. Dutta, P. et al. Myocardial infarction activates CCR2+ hematopoietic stem and progenitor cells. Cell Stem Cell 16, 477–487 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  185. Heidt, T. et al. Chronic variable stress activates hematopoietic stem cells. Nat. Med. 20, 754–758 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Hoogeveen, R. M. et al. Monocyte and haematopoietic progenitor reprogramming as common mechanism underlying chronic inflammatory and cardiovascular diseases. Eur. Heart J. 39, 3521–3527 (2018).

    CAS  PubMed  Google Scholar 

  187. van der Valk, F. M. et al. Increased haematopoietic activity in patients with atherosclerosis. Eur. Heart J. 38, 425–432 (2017).

    PubMed  Google Scholar 

  188. Musher, D. M., Abers, M. S. & Corrales-Medina, V. F. Acute infection and myocardial infarction. N. Engl. J. Med. 380, 171–176 (2019).

    CAS  PubMed  Google Scholar 

  189. Gotsman, I. & Lichtman, A. H. Targeting interferon-γ to treat atherosclerosis. Circ. Res. 101, 333–334 (2007).

    CAS  PubMed  Google Scholar 

  190. Akita, K. et al. An interleukin-6 receptor antibody suppresses atherosclerosis in atherogenic mice. Front. Cardiovasc. Med. 4, 84 (2017).

    PubMed  PubMed Central  Google Scholar 

  191. Schuett, H. et al. Transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice. Arterioscler. Thromb. Vasc. Biol. 32, 281–290 (2012).

    CAS  PubMed  Google Scholar 

  192. Slaney, C. Y., Wang, P., Darcy, P. K. & Kershaw, M. H. CARs versus BiTEs: a comparison between T cell-redirection strategies for cancer treatment. Cancer Discov. 8, 924–934 (2018).

    CAS  PubMed  Google Scholar 

  193. Koga, N. et al. Blockade of the interaction between PD-1 and PD-L1 accelerates graft arterial disease in cardiac allografts. Arterioscler. Thromb. Vasc. Biol. 24, 2057–2062 (2004).

    CAS  PubMed  Google Scholar 

  194. Zhang, H. et al. Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis. Proc. Natl Acad. Sci. USA 114, E970–E979 (2017).

    CAS  PubMed  Google Scholar 

  195. Weyand, C. M., Berry, G. J. & Goronzy, J. J. The immunoinhibitory PD-1/PD-L1 pathway in inflammatory blood vessel disease. J. Leukoc. Biol. 103, 565–575 (2018).

    CAS  PubMed  Google Scholar 

  196. Goldstein, B. L., Gedmintas, L. & Todd, D. J. Drug-associated polymyalgia rheumatica/giant cell arteritis occurring in two patients after treatment with ipilimumab, an antagonist of CTLA-4. Arthritis Rheumatol. 66, 768–769 (2014).

    PubMed  Google Scholar 

  197. Padda, A. et al. Ipilimumab induced digital vasculitis. J. Immunother. Cancer 6, 12 (2018).

    PubMed  PubMed Central  Google Scholar 

  198. Kang, A., Yuen, M. & Lee, D. J. Nivolumab-induced systemic vasculitis. JAAD Case Rep. 4, 606–608 (2018).

    PubMed  PubMed Central  Google Scholar 

  199. Laubli, H. et al. Cerebral vasculitis mimicking intracranial metastatic progression of lung cancer during PD-1 blockade. J. Immunother. Cancer 5, 46 (2017).

    PubMed  PubMed Central  Google Scholar 

  200. Loricera, J. et al. Subclinical aortitis after starting nivolumab in a patient with metastatic melanoma. A case of drug-associated aortitis? Clin. Exp. Rheumatol. 36 (Suppl. 111), 171 (2018).

    PubMed  Google Scholar 

  201. Daxini, A., Cronin, K. & Sreih, A. G. Vasculitis associated with immune checkpoint inhibitors-a systematic review. Clin. Rheumatol. 37, 2579–2584 (2018).

    PubMed  Google Scholar 

  202. Castillo, B., Gibbs, J., Brohl, A. S. & Seminario-Vidal, L. Checkpoint inhibitor-associated cutaneous small vessel vasculitis. JAAD Case Rep. 4, 675–677 (2018).

    PubMed  PubMed Central  Google Scholar 

  203. Aya, F. et al. Vasculitic neuropathy induced by pembrolizumab. Ann. Oncol. 28, 433–434 (2017).

    CAS  PubMed  Google Scholar 

  204. Bu, D. X. et al. Impairment of the programmed cell death-1 pathway increases atherosclerotic lesion development and inflammation. Arterioscler. Thromb. Vasc. Biol. 31, 1100–1107 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Gotsman, I. et al. Proatherogenic immune responses are regulated by the PD-1/PD-L pathway in mice. J. Clin. Invest. 117, 2974–2982 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Cochain, C. et al. Programmed cell death-1 deficiency exacerbates T cell activation and atherogenesis despite expansion of regulatory T cells in atherosclerosis-prone mice. PLOS ONE 9, e93280 (2014).

    PubMed  PubMed Central  Google Scholar 

  207. Hull, M. C., Morris, C. G., Pepine, C. J. & Mendenhall, N. P. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of hodgkin lymphoma treated with radiation therapy. JAMA 290, 2831–2837 (2003).

    CAS  PubMed  Google Scholar 

  208. Patel, D. A. et al. Clinical manifestations of noncoronary atherosclerotic vascular disease after moderate dose irradiation. Cancer 106, 718–725 (2006).

    PubMed  Google Scholar 

  209. Brosius, F. C. 3rd, Waller, B. F. & Roberts, W. C. 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. 70, 519–530 (1981).

    PubMed  Google Scholar 

  210. Virmani, R., Farb, A., Carter, A. J. & Jones, R. M. Pathology of radiation-induced coronary artery disease in human and pig. Cardiovasc. Radiat. Med. 1, 98–101 (1999).

    CAS  PubMed  Google Scholar 

  211. Veinot, J. P. & Edwards, W. D. Pathology of radiation-induced heart disease: a surgical and autopsy study of 27 cases. Hum. Pathol. 27, 766–773 (1996).

    CAS  PubMed  Google Scholar 

  212. Schultz-Hector, S. & Trott, K. R. Radiation-induced cardiovascular diseases: is the epidemiologic evidence compatible with the radiobiologic data? Int. J. Radiat. Oncol. Biol. Phys. 67, 10–18 (2007).

    CAS  PubMed  Google Scholar 

  213. Halle, M. et al. Sustained inflammation due to nuclear factor-kappa B activation in irradiated human arteries. J. Am. Coll. Cardiol. 55, 1227–1236 (2010).

    CAS  PubMed  Google Scholar 

  214. Christersdottir, T. et al. Prevention of radiotherapy-induced arterial inflammation by interleukin-1 blockade. Eur. Heart. J. 40, 2495–2503 (2019).

    PubMed  PubMed Central  Google Scholar 

  215. Darby, S. C. et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N. Engl. J. Med. 368, 987–998 (2013).

    CAS  PubMed  Google Scholar 

  216. Venkatesulu, B. P. et al. Radiation-induced endothelial vascular injury: a review of possible mechanisms. JACC Basic Transl. Sci. 3, 563–572 (2018).

    PubMed  PubMed Central  Google Scholar 

  217. Stewart, F. A., Seemann, I., Hoving, S. & Russell, N. S. Understanding radiation-induced cardiovascular damage and strategies for intervention. Clin. Oncol. 25, 617–624 (2013).

    CAS  Google Scholar 

  218. Stewart, F. A. et al. Ionizing radiation accelerates the development of atherosclerotic lesions in ApoE-/- mice and predisposes to an inflammatory plaque phenotype prone to hemorrhage. Am. J. Pathol. 168, 649–658 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  219. Hoving, S. et al. Single-dose and fractionated irradiation promote initiation and progression of atherosclerosis and induce an inflammatory plaque phenotype in ApoE-/- mice. Int. J. Radiat. Oncol. Biol. Phys. 71, 848–857 (2008).

    CAS  PubMed  Google Scholar 

  220. Hoving, S. et al. Anti-inflammatory and anti-thrombotic intervention strategies using atorvastatin, clopidogrel and knock-down of CD40L do not modify radiation-induced atherosclerosis in ApoE null mice. Radiother. Oncol. 101, 100–108 (2011).

    CAS  PubMed  Google Scholar 

  221. Hoving, S. et al. NO-donating aspirin and aspirin partially inhibit age-related atherosclerosis but not radiation-induced atherosclerosis in ApoE null mice. PLOS ONE 5, e12874 (2010).

    PubMed  PubMed Central  Google Scholar 

  222. Hoving, S. et al. Irradiation induces different inflammatory and thrombotic responses in carotid arteries of wildtype C57BL/6J and atherosclerosis-prone ApoE-/- mice. Radiother. Oncol. 105, 365–370 (2012).

    CAS  PubMed  Google Scholar 

  223. Hachamovitch, R., Hayes, S. W., Friedman, J. D., Cohen, I. & Berman, D. S. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 107, 2900–2907 (2003).

    PubMed  Google Scholar 

  224. Jacobse, J. N. et al. Radiation dose-response for risk of myocardial infarction in breast cancer survivors. Int. J. Radiat. Oncol. Biol. Phys. 103, 595–604 (2019).

    PubMed  PubMed Central  Google Scholar 

  225. James, M. et al. Ischaemic heart disease following conventional and hypofractionated radiation treatment in a contemporary breast cancer series. J. Med. Imaging Radiat. Oncol. 62, 425–431 (2018).

    PubMed  Google Scholar 

  226. Jagsi, R., Griffith, K. A., Koelling, T., Roberts, R. & Pierce, L. J. Rates of myocardial infarction and coronary artery disease and risk factors in patients treated with radiation therapy for early-stage breast cancer. Cancer 109, 650–657 (2007).

    PubMed  Google Scholar 

  227. Constine, L. S., Schwartz, R. G., Savage, D. E., King, V. & Muhs, A. Cardiac function, perfusion, and morbidity in irradiated long-term survivors of Hodgkin’s disease. Int. J. Radiat. Oncol. Biol. Phys. 39, 897–906 (1997).

    CAS  PubMed  Google Scholar 

  228. Glanzmann, C., Kaufmann, P., Jenni, R., Hess, O. M. & Huguenin, P. Cardiac risk after mediastinal irradiation for Hodgkin’s disease. Radiother. Oncol. 46, 51–62 (1998).

    CAS  PubMed  Google Scholar 

  229. Apter, S. et al. Cardiovascular calcifications after radiation therapy for Hodgkin lymphoma: computed tomography detection and clinical correlation. Coron. Artery Dis. 17, 145–151 (2006).

    PubMed  Google Scholar 

  230. Hicks, G. L. Jr. Coronary artery operation in radiation-associated atherosclerosis: long-term follow-up. Ann. Thorac. Surg. 53, 670–674 (1992).

    PubMed  Google Scholar 

  231. Fender, E. A. et al. Coronary artery bypass grafting in patients treated with thoracic radiation: a case-control study. Open Heart 5, e000766 (2018).

    PubMed  PubMed Central  Google Scholar 

  232. Fender, E. A. et al. Percutaneous revascularization in patients treated with thoracic radiation for cancer. Am. Heart J. 187, 98–103 (2017).

    PubMed  Google Scholar 

  233. Liang, J. J. et al. Outcomes after percutaneous coronary intervention with stents in patients treated with thoracic external beam radiation for cancer. JACC Cardiovasc. Interv. 7, 1412–1420 (2014).

    PubMed  Google Scholar 

  234. Baban, B., Liu, J. Y., Qin, X., Weintraub, N. L. & Mozaffari, M. S. Upregulation of programmed death-1 and its ligand in cardiac injury models: interaction with GADD153. PLOS ONE 10, e0124059 (2015).

    PubMed  PubMed Central  Google Scholar 

  235. Arai, A. E. Healing after myocardial infarction: a loosely defined process. JACC Cardiovasc. Imaging 8, 680–683 (2015).

    PubMed  Google Scholar 

  236. Khorana, A. A., Carrier, M., Garcia, D. A. & Lee, A. Y. Guidance for the prevention and treatment of cancer-associated venous thromboembolism. J. Thromb. Thrombolysis 41, 81–91 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. van Es, N. et al. Comparison of risk prediction scores for venous thromboembolism in cancer patients: a prospective cohort study. Haematologica 102, 1494–1501 (2017).

    PubMed  PubMed Central  Google Scholar 

  238. Totzeck, M., Mincu, R. I. & 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. 6, e006278 (2017).

    PubMed  PubMed Central  Google Scholar 

  239. Totzeck, M., Mincu, R. I., Mrotzek, S., Schadendorf, D. & Rassaf, T. Cardiovascular diseases in patients receiving small molecules with anti-vascular endothelial growth factor activity: a meta-analysis of approximately 29,000 cancer patients. Eur. J. Prev. Cardiol. 25, 482–494 (2018).

    PubMed  Google Scholar 

  240. Streiff, M. B. NCCN guidelines. Cancer-associated venous thromboembolic disease. NCCN https://www.nccn.org/professionals/physician_gls/default.aspx#supportive (2019).

  241. Agnelli, G. et al. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol. 10, 943–949 (2009).

    CAS  PubMed  Google Scholar 

  242. Verso, M., Agnelli, G., Barni, S., Gasparini, G. & LaBianca, R. A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score. Intern. Emerg. Med. 7, 291–292 (2012).

    PubMed  Google Scholar 

  243. Carrier, M. et al. Apixaban to prevent venous thromboembolism in patients with cancer. N. Engl. J. Med. 380, 711–719 (2019).

    CAS  PubMed  Google Scholar 

  244. Khorana, A. A. et al. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N. Engl. J. Med. 380, 720–728 (2019).

    CAS  PubMed  Google Scholar 

  245. Raskob, G. E. et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N. Engl. J. Med. 378, 615–624 (2018).

    CAS  PubMed  Google Scholar 

  246. Khorana, A. A. et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J. Thromb. Haemost. 16, 1891–1894 (2018).

    CAS  PubMed  Google Scholar 

  247. Montani, D. et al. Pulmonary arterial hypertension in patients treated by dasatinib. Circulation 125, 2128–2137 (2012).

    CAS  PubMed  Google Scholar 

  248. Guignabert, C. et al. Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertension. J. Clin. Invest. 126, 3207–3218 (2016).

    PubMed  PubMed Central  Google Scholar 

  249. Weatherald, J., Chaumais, M. C. & Montani, D. Pulmonary arterial hypertension induced by tyrosine kinase inhibitors. Curr. Opin. Pulm. Med. 23, 392–397 (2017).

    CAS  PubMed  Google Scholar 

  250. Weatherald, J. et al. Long-term outcomes of dasatinib-induced pulmonary arterial hypertension: a population-based study. Eur. Respir. J. 50, 1700217 (2017).

    PubMed  Google Scholar 

  251. Simonneau, G. et al. Haemodynamic definitions and updated clinical classification of pulmonary hypertension. Eur. Respir. J. 53, 1801913 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  252. Herrmann, J. et al. Vascular toxicities of cancer therapies: the old and the new – an evolving avenue. Circulation 133, 1272–1289 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Navi, B. B. et al. Arterial thromboembolic events preceding the diagnosis of cancer in older persons. Blood 133, 781–789 (2019).

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The author received and receives support from the NIH (HL116952 and CA233610) and the Miami Heart Research Institute/Florida Heart Research Foundation.

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  1. Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA

    Joerg Herrmann

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Glossary

Systemic inflammatory response syndrome

A widespread inflammatory response that might or might not be associated with infection, characterized by an abnormal temperature (>38 °C or <36 °C) and/or leukocyte count (white blood cells >1,200 per mm3, <4,000 per mm3 or bandaemia ≥10%) and either tachycardia (heart rate >90 bpm) or tachypnoea (respiratory rate >20 breaths per min).

Chimeric antigen receptor T cell therapy

(CAR T cell therapy). Strategy in which T cells harvested from a patient are genetically modified to recognize a specific tumour antigen in an antibody-like fashion, followed by activation of the engineered T cells before administration to the patient. Second-generation and third-generation CAR T cells have improved co-stimulatory domains, and fourth-generation CAR T cells (also known as armoured CAR T cells) express factors that enhance T cell expansion, persistence and anti-humoural activity.

Bispecific T cell engager therapy

(BiTE therapy). Antibody constructs designed to create an immunological synapse between an effector T cell and a tumour cell by simultaneously binding to the T cell-activation molecule CD3 and a tumour-associated antigen, which is CD19 on B cells in the case of blinatumomab (approved for the treatment of B cell acute lymphoblastic leukaemia).

Immune checkpoint inhibitor therapy

(ICI therapy). Therapy that targets internal T cell inhibitory signals known as immune checkpoints, which control T cell activity in a balance with co-stimulatory signals upon T cell receptor activation following antigen presentation and recognition. Tumours can express ligands for immune checkpoint pathways, such as programmed cell death 1, thereby mediating resistance to T cell-mediated destruction. ICIs can reverse this T cell tolerance towards tumour cells and promote T cell antitumour activity.

Virchow’s triad

Concept named after the German pathologist Rudolf Virchow, who, in 1856, described three factors that are critically important in the development of venous thrombosis: stasis, hypercoagulability and endothelial or vascular injury.

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Herrmann, J. Vascular toxic effects of cancer therapies. Nat Rev Cardiol 17, 503–522 (2020). https://doi.org/10.1038/s41569-020-0347-2

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