Advances in Understanding the Molecular Mechanisms of the Cardiovascular Toxicity of Targeted Cancer Therapies

doi:10.3969/j.issn.1007-9572.2018.00.246

Abstract

Abstract: Molecular targeted therapy is a revolutionary approach in cancer treatment that improves the quality of life of patients and prolongs patient life.However，targeted drugs often have cardiovascular toxicity.In this article，we review the adverse cardiovascular events associated with targeted therapies，including cardiac dysfunction and heart failure，arrhythmias，pulmonary hypertension，hypertension，arterial and venous ischemia and hemorrhage.We also summarize the mechanisms that contribute to the cardiovascular side effects of target drugs.

Key words: Neoplasms, Antineoplastic agents, Cardiovascular diseases, Toxic side effects, Review

摘要： 分子靶向治疗是癌症治疗革命性改变，其提高了患者生活质量，延长了患者寿命，但此类药物多具有心血管毒性。本文总结了与靶向治疗相关的心血管不良事件，包括心功能障碍、心力衰竭、心律失常、肺动脉高压、高血压以及动脉和静脉缺血、出血，总结了造成心血管毒副作用的相关机制，旨在为今后的研究提供帮助。

关键词: 肿瘤, 抗肿瘤药, 心血管疾病, 毒副作用, 综述

QI Hong-tao,PENG Zong-yu. Advances in Understanding the Molecular Mechanisms of the Cardiovascular Toxicity of Targeted Cancer Therapies[J]. Chinese General Practice, 2018, 21(27): 3403-3406. DOI: 10.3969/j.issn.1007-9572.2018.00.246.
齐洪涛,彭宗玉. 癌症靶向治疗后心血管毒副作用的分子机制研究进展[J]. 中国全科医学, 2018, 21(27): 3403-3406. DOI: 10.3969/j.issn.1007-9572.2018.00.246.

References

［1］CHANG H M，MOUDGIL R，SCARABELLI T，et al.Cardiovascular complications of cancer therapy：best practices in diagnosis，prevention，and management：part 1［J］.J Am Coll Cardiol，2017，70（20）：2536-2551.DOI：10.1016/j.jacc.2017.09.1096.3405
［2］ESCALANTE C P，CHANG Y C，LIAO K，et al.Meta-analysis of cardiovascular toxicity risks in cancer patients on selected targeted agents［J］.Support Care Cancer，2016，24（9）：4057–4074 .DOI：10.1007/s00520-016-3310-3.3405
［3］CHOUEIRI T K，MAYER E L，JE Y，et al.Congestive heart failure risk in patients with breast cancer treated with bevacizumab［J］.J Clin Oncol，2011，29（6）：632–638.DOI：10.1200/JCO.2010.31.9129.3405
［4］BIANCO C M，Al-KINDI S G，OLIVEIRA G H，et al.Advanced heart failure therapies for cancer therapeutics– related cardiac dysfunction［J］.Heart Fail Clin，2017，13（2）：327-336.DOI：10.1016/j.hfc.2016.12.005.3405
［5］KROP I E，SUTER T M，DANG C T，et al.Feasibility and cardiac safety of trastuzumab emtansine after anthracycline-based chemotherapy as （neo）adjuvant therapy for human epidermal growth factor receptor 2-positive early-stage breast cancer［J］.J Clin Oncol，2015，33（10）：1136–1142.DOI：10.1200/JCO.2014.58.7782.3405
［6］SENDUR M A，AKSOY S，ALTUNDAG K.Cardiotoxicity of novel HER2-targeted therapies［J］.Curr Med Res Opin，2013，29（8）：1015-1024.DOI：10.1185/03007995.2013.807232.3405
［7］BLOOM M W，HAMO C E，CARDINALE D，et al.Cancer therapy-related cardiac dysfunction and heart failure：part 1：definitions，pathophysiology，risk factors，and imaging［J］.Circ Heart Fail，2016，9（1）：e002661.DOI：10.1161/CIRCHEARTFAILURE.115.002661.3405
［8］KLOTH J S，PAGANI A，VERBOOM M C，et al.Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors［J］.Br J Cancer，2015，112（6）：1011–1016.DOI：10.1038/bjc.2015.82.3406
［9］TAMARGO J，CABALLERO R，DELPON E.Cancer chemotherapy and cardiac arrhythmias：a review［J］.Drug Saf，2015，38（2）：129-152.DOI：10.1007/s40264-014-0258-4.3406
［10］FRADLEY M G，PINILLA-IBARZ J.Arrhythmic complications of tyrosine kinase inhibitors［J］.Future Cardiol，2015，11（4）：395-399.DOI：10.2217/FCA.15.42.3406
［11］BUZA V，RAJAGOPALAN B，CURTIS A B.Cancer treatment-induced arrhythmias focus on chemotherapy and targeted therapies［J］.Circ Arrhythm Electrophysiol，2017，10（8）：e005443.DOI：10.1161/CIRCEP.117.005443.3406
［12］MARKMAN T M，NAZARAN S.Arrhythmia and electrophysiological effects of chemotherapy：a review［J］.Oncology，2016，91（2）：61-68.DOI：10.1159/000446374.3406
［13］VIGANEGO F，SINGH R，FRADLEY M G.Arrhythmias and other electrophysiology issues in cancer patients receiving chemotherapy or radiation［J］.Curr Cardiol Rep，2016，18（6）：52.DOI：10.1007/s11886-016-0730-0.3406
［14］SHAH N P，WALLIS N，FARBER H W，et al.Clinical features of pulmonary arterial hypertension in patients receiving dasatinib［J］.Am J Hematol，2015，90（11）：1060–1064.DOI：10.1002/ajh.24174.3406
［15］TAJIRI K，AONUMA K，SEKINE I.Cardiovascular toxic effects of targeted cancer therapy［J］.Jpn J Clin Oncol，2017，5（20）：1-7.DOI：10.1093/jjco/hyx071.3406
［16］MCGEE M，WHITEHEAD N，MARTIN J，et al.Drug-associated pulmonary arterial hypertension［J］.Clin Toxicol（Phila），2018，6（5）：1-9.DOI：10.1080/15563650.2018.1447119.3406
［17］GUIGNABERT C，PHAN C，SEFERIAN A，et al.Dasatinib induces lung vascular toxicity and predisposes to pulmonary hypertention［J］.J Clin Invest，2016，126（9）：3207-3218.DOI：10.1172/JCI86249.3406
［18］SUNDARARAJAN S，KUMAR A，POONGKUNRAN M，et al.Cardiovascular adverse effects of targeted antiangiogenic drugs：mechanisms and management［J］.Future Oncol，2016，12（8）：1067-1080.DOI：10.2217/fon.16.4.3406
［19］MOSLEHI J J，DEININGER M.Tyrosine kinase inhibitor-associated cardiovascular toxicity in chronic myeloid leukemia［J］.J Clin Oncol，2015，33（35）：4210-4218.DOI：10.1200/JCO.2015.62.4718.3406
［20］ABDEL-QADIR H，ETHIER J L，LEE D S，et al.Cardiovascular toxicity of angiogenesis inhibitors in treatment of malignancy：a systematic review and meta-analysis［J］.Cancer Treat Rev，2017，53：120-127.DOI：10.1016/j.ctrv.2016.12.002.3406
［21］BOSSAER J B，GERACI S A，CHAKRABORTY K.Cardiovascular toxicity and management of targeted cancer therapy［J］.Am J Med Sci，2016，351（5）：535-543.DOI：10.1016/j.amjms.2016.02.023.3406
［22］HERRMANN J，YANG E H，IIIESCU C A，et al.Vascular toxicities of cancer therapies：the old and new——an evolving avenue［J］.Circulation，2016，133（13）：1272-1289.DOI：10.1161/CIRCULATIONAHA.115.018347.3406
［23］RANPURA V，HAPANI S，CHUANG J，et al.Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients：a meta-analysis of randomized controlled trials［J］.Acta Oncol，2010，49（3）：287–297.DOI：10.3109/02841860903524396.3406
［24］QI W X，SHEN Z，TANG L N，et al.Risk of arterial thromboembolic events with vascular endothelial growth factor receptor tyrosine kinase inhibitors：an up-to-date meta-analysis［J］.Crit Rev Oncol Hematol，2014，92（2）：71–82.DOI：10.1016/j.critrevonc.2014.04.004.3406
［25］HAGUET H，DOUXFILS J，MULLIER F.Risk of arterial and venous occlusive events in chronic myeloid leukemia patients treated with new generation BCR-ABL tyrosine kinase inhibitors：a systematic review and meta-analysis［J］.Expert Opin Drug Saf，2017，16（1）：5-12.DOI：10.1080/14740338.2017.1261824.3406
［26］WINNIK S，LOHMANN C，SICILIANI G，et al.Systemic VEGF inhibition accelerates experimental atherosclerosis and disrupts endothelial homeostasis—implications for cardiovascular safety［J］.Int J Cardiol，2013，168（3）：2453–2461.DOI：10.1016/j.ijcard.2013.03.010.3406
［27］LOREN C P，ASLAN J E，RIGG R A，et al.The BCR-ABL inhibitor ponatinib inhibits platelet immunoreceptor tyrosine-based activation motif（ITAM） signaling，platelet activation and aggregate formation under shear［J］.Thromb Res，2015，135（1）：155–160.DOI：10.1016/j.thromres.2014.11.009.3406
［28］GOPAL S，MILLER K B，JAFFE I Z.Molecular mechanisms for vascular complications of targeted cancer therapies［J］.Clin Sci，2016，130（20）：1763-1779.DOI：10.1042/CS20160246.3406
［29］HAPANI S，SHER A，CHU D，et al.Increased risk of serious hemorrhage with bevacizumab in cancer patients：a meta-analysis［J］.Oncology，2010，79（1/2）：27–38.DOI：10.1159/000314980.3406
［30］HANG X F，XU W S，WANG J X，et al.Risk of high-grade bleeding in patients with cancer treated with bevacizumab：a meta-analysis of randomized controlled trials［J］.Eur J Clin Pharmacol，2011，67（6）：613–623.DOI：10.1007/s00228-010-0988-x.3406
［31］HENNING R J，HARBISON R D.Cardio-oncology：cardiovascular complications of cancer therapy［J］.Future Cardiol，2017，13（4）：379-396.DOI：10.2217/fca-2016-0081.3406
［32］KILICKAP S，ABALI H，CELIK I.Bevacizumab，bleeding，thrombosis，and warfarin［J］.J Clin Oncol，2003，21（18）：3542.DOI：10.1200/JCO.2003.99.046.3406

[1]	LI Qianqian, CHEN Xunrui, ZHANG Wenying, YUAN Haihua, ZHANG Yanjie, JIANG Bin, LIU Feng. Demand and Influencing Factors for Community Health Services during Chemotherapy of Patients with Advanced Cancer [J]. Chinese General Practice, 2023, 26(33): 4173-4180.
[2]	YU Xinyan, ZHAO Jun, ZHAO Xiaoye, JIANG Qingru, CHEN Yatian, WANG Yan, ZHANG Haicheng. Application of Mobile Smart Healthcare in the Prevention and Control of Cardiovascular Diseases in Elderly Patients with Chronic Diseases in Primary Care [J]. Chinese General Practice, 2023, 26(33): 4167-4172.
[3]	LI Yujing, JIN Yichao, CHEN Xing, JI Mengying, DAI Huihua. Risk Factors for Endometrial Lesions Detected by Hysteroscopy in Breast Cancer Patients Taking Tamoxifen [J]. Chinese General Practice, 2023, 26(32): 4026-4030.
[4]	GAO Dekang, WEI Shaohua, MA Xiaoming, DU Peng, XING Chungen, CAO Chun. Risk Factors for Loss of Skeletal Muscle Mass and Its Correlation with Complications after Major Hepatectomy for Liver Cancer [J]. Chinese General Practice, 2023, 26(32): 4031-4037.
[5]	ZHANG Jifang, CHEN Fang, TANG Jiawen, LI Hongliang. Predictive Value of Tumor Budding and Tumor-infiltrating Lymphocytes on Lymph Node Metastasis of Esophageal Squamous Cell Carcinoma [J]. Chinese General Practice, 2023, 26(32): 4038-4042.
[6]	ZHANG Ming, XU Jing, SUN Zhenhua, ZHAO Wenhao, MA Yingqian, ZHANG Jianqiao, SHEN Haiping. Improvement of Nutritional Status of Elderly Patients with Severe Obstruction Esophageal Carcinoma by Image-guided Photodynamic Therapy [J]. Chinese General Practice, 2023, 26(30): 3780-3784.
[7]	LI Jilei, LI Honglin, XU Yanchao, LIU Yanan, CHEN Mengli, SHAO Shuai, MA Chunzheng. Clinical Study on the Combination of Xiaotan Huayu Tongyi Granules, Channel Kaijie Pills and Chemotherapy in the Treatment of Esophageal Cancer [J]. Chinese General Practice, 2023, 26(30): 3759-3764.
[8]	ZHENG Yuling, ZHANG Yaling, LIU Huaimin, XU Yanchao, JIA Xiaolin, LI Junsai, HE Wenlong, TONG Xinduo, QIN Shanwen, ZHANG Lihan. Clinical Observation of Dingxiang Guanshitong Hanhua Pills Alone and Its Combination with Fugui Guanshitong Granules in the Treatment of Advanced Esophageal Cancer [J]. Chinese General Practice, 2023, 26(30): 3765-3771.
[9]	PAN Yaojia, WANG Weiqiang, YI Weizhuo, GAO Bing, FU Fanglin, HAN Zheng, SUN Meng, DONG Yaqin, GU Huaicong. Relationship between Triglyceride-glucose Index and Risk of Cardiovascular Diseases in Middle-aged Obese Residents of Different Genders [J]. Chinese General Practice, 2023, 26(29): 3628-3635.
[10]	PEI Bei, CHENG Lin, XU Lingyun. Effects of Different Neoadjuvant Chemotherapy Regimens on Immune Indicators and Tumor Microenvironment in HER-2-positive Breast Cancer Patients [J]. Chinese General Practice, 2023, 26(27): 3435-3440.
[11]	GAO Rongjian, WU Haili, BI Jianhong, KANG Kai, GUO Xing, LIU Juan, LI Xiaoli, MENG Cunying. Related Factors of Pathological Upgrading in Gastric Mucosal Lesions after Endoscopic Submucosal Dissection [J]. Chinese General Practice, 2023, 26(26): 3325-3329.
[12]	JI Mengying, LI Yujing, CHEN Xing, DAI Huihua, SUN Ying. Prediction Value of B-ultrasound with Tumor Markers for Malignant Transformation of Mucinous Ovarian Tumors [J]. Chinese General Practice, 2023, 26(24): 3022-3027.
[13]	WANG Rui, WANG Xiaomei, PENG Guoqing, YU Huan, WANG Sihan, XIA Jin. Screening Assessment and Therapy Intervention of Cancer Cachexia in Adult Patients——Based on the Interpretation of Cancer Cachexia in Adult Patients: ESMO Clinical Practice Guidelines [J]. Chinese General Practice, 2023, 26(23): 2823-2829.
[14]	XUE Shan, LI Laiyou, LIANG Junli, JIN Yinghui, WEI Shuyan. The Efficacy and Safety of Home Enteral Nutrition in Patients with Esophageal Cancer: a Meta-analysis [J]. Chinese General Practice, 2023, 26(20): 2540-2547.
[15]	ZHANG Yushuang, KONG Lingyang, GUAN Jiachang, LI Jianbo, WANG Yiran, WANG Yu, LI Jing. 16S rDNA Sequence Analysis of the Characteristics of Gut Flora in Patients with Esophageal Squamous Cell Carcinoma [J]. Chinese General Practice, 2023, 26(20): 2496-2502.