Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin.
Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin.
Am J Physiol Heart Circ Physiol. 2019 Oct 1;317(4):H705-H710. doi: 10.1152/ajpheart.00370.2019. Epub 2019 Aug 9.
Chemotherapy (CT) is a necessary treatment to prevent the growth and survival of cancer cells. However, CT has a well-established adverse impact on the cardiovascular (CV) system, even years after cessation of treatment. The effects of CT drugs on tumor vasculature have been the focus of much research, but little evidence exists showing the effects on the host microcirculation. Microvascular (MV) dysfunction is an early indicator of numerous CV disease phenotypes, including heart failure. The goal of this study was to evaluate the direct effect of doxorubicin (Dox) on human coronary MV function. To study the effect of CT on the cardiac MV function, flow-mediated dilation (FMD), pharmacologically-induced endothelial dependent dilation to acetylcholine (ACh), and smooth muscle-dependent dilation to papaverine were investigated. Vessels were freshly isolated from atrial appendages of adult patients undergoing cardiopulmonary bypass surgery or from cardiac tissue of pediatric patients, collected at the time of surgery to repair congenital heart defects. Isolated vessels were incubated in endothelial culture medium containing vehicle or Dox (100 nm, 15-20 h) and used to measure dilator function by video microscopy. Ex vivo treatment of adult human coronary microvessels with Dox significantly impaired flow-mediated dilation (FMD). Conversely, in pediatric coronary microvessels, Dox-induced impairment of FMD was significantly reduced in comparison with adult subjects. In both adult and pediatric coronary microvessels, ACh-induced constriction was reversed into dilation in the presence of Dox. Smooth muscle-dependent dilation remained unchanged in all groups tested. In vessels from adult subjects, acute treatment with Dox in clinically relevant doses caused significant impairment of coronary arteriolar function, whereas vessels from pediatric subjects showed only marginal impairment to the same stressor. This interesting finding might explain the delayed onset of future adverse CV events in children compared with adults after anthracycline therapy. We have characterized, for the first time, human microvascular responses to acute ex vivo exposure to doxorubicin in coronary vessels from patients without cancer. Our data show an augmented impairment of endothelial function in vessels from adult subjects compared with pediatric samples.
化疗（CT）是预防癌细胞生长和存活的必要治疗方法。然而，CT 对心血管（CV）系统有明确的不良影响，甚至在治疗停止多年后也是如此。CT 药物对肿瘤血管的影响一直是许多研究的焦点，但几乎没有证据表明其对宿主微循环的影响。微血管（MV）功能障碍是许多心血管疾病表型的早期指标，包括心力衰竭。本研究的目的是评估多柔比星（Dox）对人冠状动脉 MV 功能的直接影响。为了研究 CT 对心脏 MV 功能的影响，研究了血流介导的扩张（FMD）、乙酰胆碱（ACh）诱导的内皮依赖性扩张、罂粟碱诱导的平滑肌依赖性扩张。血管从接受心肺旁路手术的成年患者的心房附件或接受先天性心脏缺陷修复手术的儿科患者的心脏组织中新鲜分离出来。分离的血管在含有载体或 Dox（100nm，15-20h）的内皮培养培养基中孵育，并通过视频显微镜测量扩张功能。用 Dox 体外处理成人冠状动脉微血管，明显损害血流介导的扩张（FMD）。相反，在儿科冠状动脉微血管中，与成年患者相比，Dox 诱导的 FMD 损害明显减少。在所有测试的成年和儿科冠状动脉微血管中，ACh 诱导的收缩在 Dox 存在的情况下被逆转为扩张。在所有测试的血管中，平滑肌依赖性扩张保持不变。在接受临床相关剂量的 Dox 急性治疗的成年患者的血管中，导致冠状动脉小动脉功能明显受损，而儿科患者的血管对同一应激因素仅显示出轻微受损。这一有趣的发现可能解释了与接受蒽环类药物治疗的成年人相比，儿童在接受蒽环类药物治疗后未来不良心血管事件的延迟发生。我们首次描述了来自无癌症患者的冠状动脉中人类微血管对急性体外暴露于多柔比星的反应。我们的数据显示，与儿科样本相比，成年患者的血管内皮功能受损程度更大。
