Wachtman Lynn M, Browning Michelle D, Bedja Djahida, Pin Scott, Gabrielson Kathleen L
Department of Molecular and Comparative Pathobiology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
J Am Assoc Lab Anim Sci. 2006 Sep;45(5):55-64.
Doxorubicin administered to rats induces a dose-dependent cardiomyopathy. Both doxorubicin administration and the presence of indwelling catheters have been associated with thrombus formation. We sought to determine feasibility of drug delivery and degree of thrombogenesis related to long-term indwelling catheter use in a cardiotoxicity model. Rats receiving doxorubicin or saline via jugular catheters coated with end-point immobilized heparin were compared to rats receiving similar treatments via direct jugular intravenous injection (venotomy). Onset of cardiotoxicity, defined by reduction in fractional shortening to 45% or less, was determined by echocardiography. Thrombogenesis was assessed by observation of atrial thrombi and pulmonary emboli as determined by post-mortem and histologic examination. Significantly more of the doxorubicin-treated and catheterized group (87.5%) developed cardiotoxicity relative to the doxorubicin-treated-venotomized group (28.6%), as indicated by an earlier and more precipitous decline in fractional shortening in the doxorubicin-treated-catheterized rats. Despite this change, rats from catheterized groups demonstrated improved weight maintenance relative to venotomy groups. Although the number of pulmonary emboli did not differ significantly between groups, 50% of the doxorubicin-treated-catheterized animals developed vegetative endocarditis. Despite alteration of the model-induced cardiac disease, we submit that the more reliable and early induction of the desired endpoint, in addition to improved weight maintenance, represent model refinements. The ease of drug delivery with minimal restraint and no anesthesia is an additional and important benefit. The development of vegetative endocarditis represents an opportunity to study the formation and prevention of this condition.
给大鼠注射阿霉素会诱发剂量依赖性心肌病。阿霉素给药以及留置导管的存在均与血栓形成有关。我们试图确定在心脏毒性模型中与长期使用留置导管相关的药物递送可行性和血栓形成程度。将通过涂有终点固定化肝素的颈静脉导管接受阿霉素或生理盐水的大鼠与通过直接颈静脉静脉注射（静脉切开术）接受类似治疗的大鼠进行比较。通过超声心动图确定心脏毒性的发作，以缩短分数降低至45%或更低来定义。通过尸检和组织学检查确定的心房血栓和肺栓塞观察来评估血栓形成。与阿霉素治疗的静脉切开术组（28.6%）相比，阿霉素治疗并插管的组中出现心脏毒性的比例显著更高（87.5%），阿霉素治疗并插管的大鼠缩短分数下降更早且更急剧。尽管有这种变化，但插管组的大鼠相对于静脉切开术组在体重维持方面有所改善。尽管各组之间肺栓塞的数量没有显著差异，但50%的阿霉素治疗并插管的动物发生了赘生性心内膜炎。尽管模型诱导的心脏疾病有所改变，但我们认为除了改善体重维持外，更可靠且早期诱导出所需终点代表了模型的改进。以最小的限制且无需麻醉即可轻松进行药物递送是另一个重要优点。赘生性心内膜炎的发生为研究这种病症的形成和预防提供了机会。
