Damage to cardiac vasculature may be associated with breast cancer treatment-induced cardiotoxicity.
Damage to cardiac vasculature may be associated with breast cancer treatment-induced cardiotoxicity.
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DOI：
10.1186/s40959-021-00100-3
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发表时间：
2021-04-19
期刊：
影响因子：
--
通讯作者：
Ryeom S
中科院分区：
文献类型：
--
作者：
Hoffman RK;Kim BJ;Shah PD;Carver J;Ky B;Ryeom S
乳腺癌是全世界最常见的女性癌症。包括阿霉素和曲妥珠单抗在内的有效治疗方法提高了存活率，但与心血管疾病的重大风险有关。癌症治疗所致心脏毒性(CTC)的机制目前知之甚少，主要集中在心肌细胞损伤上，尽管心脏中的其他细胞群，如心脏内皮细胞，可能在心脏损伤中发挥重要作用。我们用阿霉素和曲妥珠单抗治疗荷乳腺肿瘤的小鼠模型，研究心脏内皮细胞在CTC发生发展中的作用。将高表达HER2的人乳腺癌细胞(BT474)接种于免疫缺陷小鼠的第4乳房脂肪垫内。当肿瘤可触及时，每周给予阿霉素(5 mg/kg)和曲妥珠单抗(4 mg/kg)治疗。通过超声心动图和心脏组织学评价评价小鼠的心脏表型。用体内通透性试验检测心脏血管损伤，用原代培养的小鼠心肌内皮细胞测定阿霉素的体外毒性。阿霉素和曲妥珠单抗可抑制Balb/c裸鼠BT474乳腺肿瘤的生长。用阿霉素和曲妥珠单抗治疗4个 月的小鼠保持了体重，但超声心动图表型与保留的左心室射血分数(LV)一致，减少了LV质量和增加了充盈压力(E/E‘)。马森氏三色和天狼星红组织学染色显示，与未治疗的小鼠相比，治疗组小鼠血管周围的心肌中广泛的纤维化和胶原沉积增加。伊文思蓝通透性测定显示心脏血管通透性增加，而体外培养的原代心脏内皮细胞与肺或肝内皮细胞相比，暴露于阿霉素后细胞死亡增加。阿霉素和曲妥珠单抗联合治疗的裸鼠原位人乳腺癌模型出现心脏血管缺陷，并伴有左心室射血分数保留，左心室重量减少，提示轻度的舒张期功能障碍和心脏重构符合亚临床心脏毒性。我们的数据提示，与其他器官内皮相比，心脏内皮细胞对阿霉素治疗更敏感，心脏内皮损伤可能与乳腺癌治疗引起的心脏毒性有关。
Breast cancer is the most common female cancer worldwide. Effective therapies including doxorubicin and trastuzumab have improved survival, but are associated with a substantial risk of cardiovascular disease. Mechanisms underlying cancer treatment-induced cardiotoxicity (CTC) are poorly understood and have largely focused on cardiomyocyte damage, although other cellular populations in the heart such as the cardiac endothelium, may play an important role in cardiac damage. We treated a breast tumor-bearing mouse model with doxorubicin and trastuzumab to investigate the role of the cardiac endothelium in the development of CTC. Immune compromised mice were inoculated in the 4th mammary fat pad with human breast cancer cells overexpressing HER2 (BT474). When tumors were palpable, mice were treated weekly with doxorubicin (5 mg/kg) and trastuzumab (4 mg/kg). The cardiac phenotype of mice was assessed by echocardiography and histological evaluation of the heart. Cardiac vascular damage was assayed by in vivo permeability assays and primary cultures of murine cardiac endothelial cells were used to assay doxorubicin toxicity in vitro. The growth of BT474 breast tumors in Balb/c Nude mice was suppressed upon treatment with doxorubicin and trastuzumab. Mice treated for 4 months with doxorubicin and trastuzumab maintained body weights, but demonstrated an echocardiographic phenotype consistent with preserved left ventricular (LV) ejection fraction, decreased LV mass and increased filling pressures (E/e’). Histological staining with Masson’s trichrome and Picrosirius red showed extensive fibrosis and increased collagen deposition in the ventricular myocardium surrounding blood vessels of treated mice compared to untreated mice. Evans blue permeability assays demonstrated increased cardiac vasculature permeability while primary cardiac endothelial cells exposed to doxorubicin in vitro showed increased cell death as compared to lung or liver endothelial cells. An orthotopic mouse model of human breast cancer in Nude mice treated with doxorubicin and trastuzumab resulted in a cardiac vascular defect accompanied by preserved LV ejection fraction, decreased LV mass, suggesting mild diastolic dysfunction and cardiac remodeling consistent with subclinical cardiotoxicity. Our data suggest that cardiac endothelium is more sensitive to doxorubicin therapy as compared to other organ endothelium and cardiac endothelial damage may correlate with breast cancer treatment-induced cardiotoxicity.
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影响因子：
7.5
作者：
Jordan, Jennifer H.;D'Agostino, Ralph B., Jr.;Hundley, W. Gregory
通讯作者：
Hundley, W. Gregory
影响因子：
6
作者：
Tarantini, Luigi;Cioffi, Giovanni;Faggiano, Pompilio
通讯作者：
Faggiano, Pompilio
影响因子：
3.7
作者：
Pentassuglia L;Sawyer DB
通讯作者：
Sawyer DB
DOI：
10.1161/circimaging.115.003584
发表时间：
2016-12
期刊：
Circulation. Cardiovascular imaging
影响因子：
--
作者：
Farhad H;Staziaki PV;Addison D;Coelho-Filho OR;Shah RV;Mitchell RN;Szilveszter B;Abbasi SA;Kwong RY;Scherrer-Crosbie M;Hoffmann U;Jerosch-Herold M;Neilan TG
通讯作者：
Neilan TG
影响因子：
24
作者：
Abdel-Qadir, Husam;Austin, Peter C.;Anderson, Geoffrey M.
通讯作者：
Anderson, Geoffrey M.