Cardiovascular and systemic microvascular effects of anti-vascular endothelial growth factor therapy for cancer.
Cardiovascular and systemic microvascular effects of anti-vascular endothelial growth factor therapy for cancer.
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DOI：
10.1016/j.jacc.2012.02.053
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发表时间：
2012-08-14
影响因子：
24
通讯作者：
Lindner, Jonathan R.
中科院分区：
文献类型：
--
作者：
Belcik, J. Todd;Qi, Yue;Kaufmann, Beat A.;Xie, Aris;Bullens, Sherry;Morgan, Terry K.;Bagby, Susan P.;Kolumam, Ganesh;Kowalski, Joe;Oyer, Jon A.;Bunting, Stuart;Lindner, Jonathan R.
本研究旨在评价微血管功能稀疏和血管力学性质变化对高血压发展和抗血管内皮生长因子（VEGF）治疗后继发性心室重构的影响。高血压是用于癌症药物的VEGF抑制剂的常见副作用。小鼠用抗鼠VEGF-A单克隆抗体、抗体加雷米普利或假处理处理5周。微血管血流量（MBF）和血容量（MBV）通过对比增强超声在骨骼肌，左心室（LV）和肾脏进行定量。采用超声心动图和有创血流动力学检查评估心室功能、尺寸和血管力学特性。动态血压在抗VEGF治疗的前3周逐渐升高。与对照组相比，抗VEGF治疗的小鼠具有相似的主动脉弹性模量和组织学外观，但动脉弹性显著增加，表明后负荷增加，血浆血管紧张素II升高。治疗组小鼠后负荷增加导致向心性LV重构和每搏输出量减少，但LV收缩力未受损，这通过LV峰值压力随时间的变化（dp/dt）和收缩末期尺寸-压力关系确定。抗VEGF治疗并没有改变骨骼肌、心肌或肾脏的MBF或MBV，但确实产生了皮质系膜肾小球硬化。雷米普利治疗几乎完全防止了抗VEGF治疗小鼠的不良血流动力学效应、后负荷增加和LV重塑。在抗VEGF治疗期间，功能性微血管密度降低或动脉机械特性的重大改变都不是高血压的主要原因。VEGF的抑制导致后负荷错配状态、血管紧张素II增加和LV重塑，这些都可通过血管紧张素转换酶抑制而改善。
This study sought to evaluate the contribution of microvascular functional rarefaction and changes in vascular mechanical properties to the development of hypertension and secondary ventricular remodeling that occurs with anti-vascular endothelial growth factor (VEGF) therapy. Hypertension is a common side effect of VEGF inhibitors used in cancer medicine. Mice were treated for 5 weeks with an anti-murine VEGF-A monoclonal antibody, antibody plus ramipril, or sham treatment. Microvascular blood flow (MBF) and blood volume (MBV) were quantified by contrast-enhanced ultrasound in skeletal muscle, left ventricle (LV), and kidney. Echocardiography and invasive hemodynamics were used to assess ventricular function, dimensions and vascular mechanical properties. Ambulatory blood pressure increased gradually over the first 3 weeks of anti-VEGF therapy. Compared with controls, anti-VEGF–treated mice had similar aortic elastic modulus and histological appearance, but a marked increase in arterial elastance, indicating increased afterload, and elevated plasma angiotensin II. Increased afterload in treated mice led to concentric LV remodeling and reduced stroke volume without impaired LV contractility determined by LV peak change in pressure over time (dp/dt) and the end-systolic dimension–pressure relation. Anti-VEGF therapy did not alter MBF or MBV in skeletal muscle, myocardium, or kidney; but did produce cortical mesangial glomerulosclerosis. Ramipril therapy almost entirely prevented the adverse hemodynamic effects, increased afterload, and LV remodeling in anti-VEGF–treated mice. Neither reduced functional microvascular density nor major alterations in arterial mechanical properties are primary causes of hypertension during anti-VEGF therapy. Inhibition of VEGF leads to an afterload mismatch state, increased angiotensin II, and LV remodeling, which are all ameliorated by angiotensin-converting enzyme inhibition.
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DOI：
10.1161/01.atv.17.11.2793
发表时间：
1997-11-01
影响因子：
8.7
作者：
Horowitz, JR;Rivard, A;Isner, JM
通讯作者：
Isner, JM
影响因子：
158.5
作者：
Eremina, Vera;Jefferson, J. Ashley;Quaggin, Susan E.
通讯作者：
Quaggin, Susan E.
影响因子：
4.8
作者：
Liang, WC;Wu, XM;Fuh, G
通讯作者：
Fuh, G
影响因子：
19.6
作者：
Hara, A.;Wada, T.;Kaneko, S.
通讯作者：
Kaneko, S.
影响因子：
15.9
作者：
Shiojima, I;Sato, K;Walsh, K
通讯作者：
Walsh, K