University of Belgrade Faculty of Medicine, Faculty of Medicine, Institute of Pharmacology, Clinical Pharmacology and Toxicology, Belgrade, Serbia.
Semmelweis University Department of Pharmacology and Pharmacotherapy, Budapest, Hungary.
Toxicol Appl Pharmacol. 2021 Jul 15;423:115579. doi: 10.1016/j.taap.2021.115579. Epub 2021 May 17.
Cardiomyopathy resistant to treatment is the most serious adverse effect of doxorubicin (dox). The mechanisms of dox-induced cardiomyopathy (DCM) have been extensively studied in dilated forms of DCM. However, efficient treatment did not emerge. The aim of the present work was to revisit the experimental model of DCM in rats, to define phenotype/s and associate them to the changes in cardiac transcriptome. Male Wistar rats equipped with radiotelemetry device, were randomized in DOX group (5 mg/0,5 mL/kg, IV dox; n = 18) and CONT group (0,5 mL/kg IV saline; n = 6). Echocardiography, autonomic spectral markers and baroreceptor reflex evaluation was performed prior to, and after treatment. Blood samples were collected at the end of experimentation. Cardiac, renal and hepatic tissues were analysed post-mortem by histology. Changes in expression of key cardiac genes affected by dox were assessed by RT-qPCR. Phenotypes were identified by clustering non-redundant features using four different algorithms averaged by evidence accumulation cluster technique. The results emphasize the existence of two major phenotypes of DCM with comparably high mortality rates: phenotype 1 characterized by, left ventricular (LV) dilatation, thinning of LV posterior wall, reduced LV ejection fraction (LVEF) and fractional shortening (LVFS), decreased HR variability (HRV), decreased baroreceptor effectiveness index (BEI) and increased NT-proBNP; and phenotype 2 with LV hypertrophy - increased LV mass, preserved LVEF, LVFS, no changes in HRV and BEI and moderate NT-proBNP increase. Both phenotypes exhibited a genetic shift to a new-born program.
治疗抵抗性心肌病是多柔比星（阿霉素）（dox）最严重的不良反应。在扩张型心肌病的 DCM 中，已经广泛研究了 dox 诱导的心肌病（DCM）的机制。然而，并没有出现有效的治疗方法。本研究的目的是重新研究大鼠 DCM 的实验模型，定义表型并将其与心脏转录组的变化相关联。雄性 Wistar 大鼠配备无线电遥测设备，随机分为 DOX 组（5 mg/0.5 mL/kg，IV 多柔比星；n=18）和 CONT 组（0，5 mL/kg IV 生理盐水；n=6）。在治疗前后进行超声心动图、自主频谱标志物和压力感受反射评估。实验结束时采集血液样本。死后分析心脏、肾脏和肝脏组织的组织学。通过 RT-qPCR 评估受 dox 影响的关键心脏基因表达的变化。通过使用证据积累聚类技术平均的四种不同算法对非冗余特征进行聚类，确定表型。结果强调了存在两种具有相当高死亡率的 DCM 主要表型：表型 1 表现为左心室（LV）扩张、LV 后壁变薄、LV 射血分数（LVEF）和缩短分数（LVFS）降低、HR 变异性（HRV）降低、压力感受反射有效性指数（BEI）降低和 NT-proBNP 增加；表型 2 为 LV 肥大 - LV 质量增加、LVEF、LVFS 保留、HRV 和 BEI 无变化和中等 NT-proBNP 增加。两种表型都表现出向新生程序的遗传转变。
