Vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (VEGFR-TKI), an oral molecular targeted drug, reportedly causes serious adverse cardiovascular events such as hypertension and left ventricular failure. The association between VEGFR-TKI-induced hypertension and heart failure with preserved left ventricular ejection fraction (LVEF) (HFpEF) has been previously studied. Therefore, we investigated the relationship between hypertension onset and associated cardiac diastolic dysfunction due to VEGFR-TKI use. Patients who used VEGFR-TKIs (target drugs: sunitinib, axitinib, sorafenib, pazopanib, and cabozantinib) at the Department of Urology, Hokkaido Cancer Center were recruited between May 2009 and October 2021 and were divided into two groups based on whether their blood pressure was elevated during VEGFR-TKI use. The markers of left ventricular diastolic function (E/A, Dct (ms), mean E/e, septal e') and left ventricular systolic function (LVEF, LVDd, and LVDs) were evaluated. LVEF and mean E/e in the elevated blood pressure group (n = 41) showed significant changes before and after treatment. LVEF values (contractile function markers) in the TKI-HT (+) group significantly decreased from 70.7% ± 6.8% before treatment to 68.3% ± 7.8% after treatment (p = 0.03). Conversely, no significant difference was observed for any ventricular systolic function marker in the TKI-HT (−) group. E/e (diastolic function marker) in the TKI-HT (+) group significantly decreased from 11.9% ± 3.6% before treatment to 10.3% ± 3.0% after treatment (p = 0.02). However, no change was observed in any ventricular diastolic function marker in the TKI-HT (−) group. The results of this study suggest that cardiac function may be affected in patients using VEGFR-TKI. Furthermore, appropriate antihypertensive treatment and early monitoring with regular echocardiography, even in asymptomatic patients, may help prevent VEGFR-TKI-induced deterioration of systolic and diastolic function.
References
[1]
Yoshimura, K., Miyagawa, Y., Yamada, R., Nishimura, K., Miyoshi, S. and Mizutani, S. (1992) Clinical Study on Incidental Renal Cell Carcinoma. Hinyokika Kiyo, 38, 143-147.
[2]
Matsuoka, M. (2017) Renal Cancer Clinical Practice Guideline 2017 Edition. The Japanese Urological Association, Tokyo, 74-76.
[3]
Qin, S., Li, A., Yi, M., Yu, S., Zhang, M. and Wu, K. (2019) Recent Advances on Anti-Angiogenesis Receptor Tyrosine Kinase Inhibitors in Cancer Therapy. Journal of Hematology & Oncology, 12, Article No. 27.
https://doi.org/10.1186/s13045-019-0718-5
[4]
Yeh, E.T.H. and Chang, H.-M. (2016) Oncocardiology—Past, Present, and Future: A Review. JAMA Cardiology, 1, 1066-1072.
https://doi.org/10.1001/jamacardio.2016.2132
[5]
Ohte, N., Ishizu, T., et al. (2022) JCS 2021 Guideline on the Clinical Application of Echocardiography, Circulation Journal, 86, 2045-2119.
https://doi.org/10.1253/circj.CJ-22-0026
[6]
Takada, M., Yasui, T., Oka, T., et al. (2018) Aortic Dissection and Cardiac Dysfunction Emerged Coincidentally During the Long-Term Treatment with Angiogenesis Inhibitors for Metastatic Renal Cell Carcinoma. International Heart Journal, 59, 1174-1179. https://doi.org/10.1536/ihj.17-461
[7]
Chu, T.F., Rupnick, M.A., Kerkela, R., Dallabrida, S.M., Zurakowski, D., Nguyen, L., Woulfe, K., Pravda, E., Cassiola, F., Desai, J., George, S., Morgan, J.A., Harris, D.M., Ismail, N.S., Chen, J.H., Schoen, F.J., Van den Abbeele, A.D., Demetri, G.D., Force, T. and Chen, M.H. (2007) Cardiotoxicity Associated with Tyrosine Kinase Inhibitor Sunitinib. Lancet, 370, 2011-2019. https://doi.org/10.1016/S0140-6736(07)61865-0
[8]
Khakoo, A.Y., Kassiotis, C.M., Tannir, N., Plana, J.C., Halushka, M., Bickford, C., Trent, J., 2nd, Champion, J.C., Durand, J.-B. and Lenihan, D.J. (2008) Heart Failure Associated with Sunitinib Malate: A Multitargeted Receptor Tyrosine Kinase Inhibitor. Cancer, 112, 2500-2508. https://doi.org/10.1002/cncr.23460
[9]
Yamamoto, K., Sakata, Y., Ohtani, T., Takeda, Y. and Mano T. (2009) Heart Failure with Preserved Ejection Fraction. Circulation Research, 73, 404-410.
https://doi.org/10.1253/circj.CJ-08-1073
[10]
Ky, B., Vejpongsa, P., Yeh, E.T., Force, T. and Moslehi, J.J. (2013) Emerging Paradigms in Cardiomyopathies Associated with Cancer Therapies. Circulation Research, 113, 754-764. https://doi.org/10.1161/CIRCRESAHA.113.300218
[11]
Liu, B., Ding, F., Liu, Y., Xiong, G., Lin, T., He, D., Zhang, Y., Zhang, D. and Wei, G. (2016) Incidence and Risk of Hypertension Associated with Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Cancer Patients: A Comprehensive Network Meta-Analysis of 72 Randomized Controlled Trials Involving 30013 Patients. Oncotarget, 7, 67661-67673.
https://doi.org/10.18632/oncotarget.11813
[12]
Kondo, T. (2012) Role of VEGFR-TKIs in the Treatment of Renal Cell Carcinoma. Nihon Jinzo Gakkai Shi, 54, 574-580. (In Japanese)
[13]
Upshaw, J.N., Finkelman, B., Hubbard, R.A., et al. (2020) Comprehensive Assessment of Changes in Left Ventricular Diastolic Function with Contemporary Breast Cancer Therapy. JACC: Cardiovascular Imaging, 13, 198-210.
https://doi.org/10.1016/j.jcmg.2019.07.018
[14]
Qi, W.-X., Shen, Z., Tang, L.-N. and Yao, Y. (2014) Congestive Heart Failure Risk in Cancer Patients Treated with Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors: A Systematic Review and Meta-Analysis of 36 Clinical Trials. British Journal of Clinical Pharmacology, 78, 748-762. https://doi.org/10.1111/bcp.12387
[15]
Wada, T., Ando, K., Naito, A.T., Nakamura, Y., Goto, A., Chiba, K., Lubna, N.J., Cao, X., Hagiwara-Nagasawa, M., Izumi-Nakaseko, H., Nakazato, Y. and Sugiyama, A. (2018) Sunitinib Does Not Acutely Alter Left Ventricular Systolic Function, but Induces Diastolic Dysfunction. Cancer Chemotherapy Pharmacology, 82, 65-75.
https://doi.org/10.1007/s00280-018-3593-9
[16]
Yokoyama, H., Shioyama, W., Shintani, T., Maeda, S., Hirobe, S., Maeda, M., Sakata, Y. and Fujio, Y. (2021) Vascular Endothelial Growth Factor Receptor Inhibitors Impair Left Ventricular Diastolic Functions. International Heart Journal, 62, 1297-1304.
https://doi.org/10.1536/ihj.21-307
[17]
Catino, A.B., Hubbard, R.A., Chirinos, J.A., Townsend, R., Keefe, S., Haas, N.B., Puzanov, I., Fang, J.C., Agarwal, N., Hyman, D., Smith, A.M., Gordon, M., Plappert, T., Englefield, V., Narayan, V., Ewer, S., ElAmm, C., Lenihan, D. and Ky, B. (2018) Longitudinal Assessment of Vascular Function with Sunitinib in Patients with Metastatic Renal Cell Carcinoma. Circulation Heart Failure, 11, e004408.
https://doi.org/10.1161/CIRCHEARTFAILURE.117.004408
[18]
Aroesty, J.M., McKay, R.G., Heller, G.V., Royal, H.D., Als, A.V. and Grossman, W. (1985) Simultaneous Assessment of Left Ventricular Systolic and Diastolic Dysfunction during Pacing-Induced Ischemia. Circulation, 71, 889-900.
https://doi.org/10.1161/01.CIR.71.5.889
