University of South Carolina School of Medicine , Columbia, South Carolina.
Connecticut Children's Medical Center , Hartford, Connecticut.
Am J Physiol Heart Circ Physiol. 2018 Nov 1;315(5):H1443-H1452. doi: 10.1152/ajpheart.00252.2018. Epub 2018 Aug 24.
Anthracycline chemotherapy (AC) is associated with decline in left ventricular ejection fraction (LVEF), yet the mechanisms remain unclear. Although changes in microRNAs (miRs) have been identified in adult cardiovascular disease, miR profiles in pediatric patients with AC have not been well studied. The goal of this study was to examine miR profiles (unbiased array) in pediatric patients with AC compared with age-matched referent normal patients. We hypothesize that pediatric patients with AC will express a unique miR profile at the initiation and completion of therapy and will be related to LVEF. Serum was collected in pediatric patients (10-22 yr, n = 12) with newly diagnosed malignancy requiring AC within 24-48 h after the initiation of therapy (30-60 mg/m) and ~1 yr after completing therapy. A custom microarray of 84 miRs associated with cardiovascular disease was used (quantitative RT-PCR) and indexed to referent normal profiles (13-17 yr, n = 17). LVEF was computed by cardiac MRI. LVEF fell from AC initiation at ~1 yr after AC completion (64.28 ± 1.78% vs. 57.53 ± 0.95%, respectively, P = 0.004). Of the 84 miRs profiled, significant shifts in 17 miRs occurred relative to referent normal ( P ≤ 0.05). Moreover, the functional domain of miRs associated with myocardial differentiation and development fell over threefold at the completion of AC ( P ≤ 0.05). Moreover, eight miRs were significantly downregulated after AC completion in those patients with the greatest decline in LVEF (≥10%, P < 0.05). This study demonstrates, for the first time, that changes in miR expression occur in pediatric patients with AC. These findings suggest that miRs are a potential strategy for the early identification of patients with AC susceptible to left ventricular dysfunction. NEW & NOTEWORTHY Although anthracycline chemotherapy (AC) is effective for a number of pediatric cancers, an all too often consequence of AC is the development of left ventricular failure. The present study identified that specific shifts in the pattern of microRNAs, which regulate myocardial growth, function, and viability, occurred during and after AC in pediatric patients, whereby the magnitude of this shift was associated with the degree of left ventricular failure.
蒽环类化疗（AC）与左心室射血分数（LVEF）下降有关，但机制尚不清楚。虽然在成人心血管疾病中已经发现了 microRNAs（miRs）的变化，但在接受 AC 的儿科患者中，miR 谱尚未得到很好的研究。本研究的目的是检查接受 AC 的儿科患者与年龄匹配的参考正常患者相比的 miR 谱（无偏阵列）。我们假设接受 AC 的儿科患者在开始和完成治疗时会表达独特的 miR 谱，并且与 LVEF 相关。在开始治疗后 24-48 小时内（30-60mg/m）和完成治疗后约 1 年，采集新诊断患有恶性肿瘤的儿科患者（10-22 岁，n=12）的血清，需要接受 AC。使用与心血管疾病相关的 84 种 miR 的定制微阵列（定量 RT-PCR）并将其索引到参考正常谱（13-17 岁，n=17）。通过心脏 MRI 计算 LVEF。LVEF 在接受 AC 后约 1 年时从接受 AC 开始时下降（分别为 64.28±1.78%和 57.53±0.95%，P=0.004）。在所分析的 84 种 miR 中，有 17 种 miR 的表达发生了显著变化，与参考正常相比（P≤0.05）。此外，在接受 AC 治疗后，与心肌分化和发育相关的 miR 功能域下降了三倍以上（P≤0.05）。此外，在 LVEF 下降≥10%的患者中，接受 AC 治疗后，有 8 种 miR 的表达显著下调（P<0.05）。本研究首次证明，AC 后儿科患者的 miR 表达发生变化。这些发现表明，miRs 是早期识别易发生左心室功能障碍的 AC 患者的潜在策略。 新的和值得注意的是，尽管蒽环类化疗（AC）对许多儿科癌症有效，但 AC 的一个常见后果是左心室衰竭的发展。本研究确定，在接受 AC 的儿科患者中，调节心肌生长、功能和存活的 microRNAs 模式发生了特定变化，并且这种变化的幅度与左心室衰竭的程度相关。
