Radiation-induced HFpEF model as a potential tool for the exploration of novel therapeutic targets.
Radiation-induced HFpEF model as a potential tool for the exploration of novel therapeutic targets.
复制标题
辐射诱导的 HFpEF 模型作为探索新治疗靶点的潜在工具。
DOI：
10.1152/ajpheart.00307.2017
复制
发表时间：
2017
期刊：
影响因子：
--
通讯作者：
Kitakaze M
中科院分区：
文献类型：
--
作者：
Tsukamoto O;Kitakaze M
乳腺癌患者的预后有所改善：近年来5年生存率约为90%(7)，部分原因是化疗和放疗等辅助治疗的使用增加。放射治疗技术的最新进展大大减少了乳腺癌放射治疗期间对心脏的辐射照射，从而减少了动脉粥样硬化引起的心血管疾病的发生率。然而，在当代乳腺癌放疗过程中，即使对心脏进行低水平的辐射照射，也会对冠状动脉微血管产生有害影响，这与心脏平均辐射剂量下保留射血分数（HFpEF）的心力衰竭风险增加有关（12）。因此，辐射诱发的心血管疾病，尤其是HFpEF，成为乳腺癌幸存者最重要的竞争死亡风险(1)。迄今为止，心脏辐射对左心室舒张功能的影响仍未明确表征。尽管先前的研究表明，在动物模型和乳腺癌患者中，心脏辐射暴露与随后的微血管稀疏之间存在联系，但尚未评估左室舒张功能（9,14）。在这一期的《美国生理学-心脏与循环生理学》杂志上，Saiki等人建立了一种新的舒张功能异常模型，该模型通过实验全心辐射36暴露，在不降低射血分数的情况下，舒张功能异常与微血管稀疏程度密切相关。虽然目前的研究没有评估辐射暴露后最早的形态学变化，但先前的研究表明，辐射主要损害微血管，然后是炎症和血栓性改变，导致毛细血管损失，从而导致心肌组织灌注低（14）。目前的研究首次显示了乳腺癌放射治疗后微血管功能障碍与HFpEF风险增加之间的因果关系。有趣的是，尽管初始触发因素完全不同，但辐射暴露相关的HFpEF模型似乎与代谢风险相关的HFpEF人类模型（4,10,16）和动物模型（5,13）具有相同的潜在机制，即一氧化氮45 (NO)-环鸟苷单磷酸(cGMP)-蛋白激酶G （PKG）信号的干扰
The prognosis of patients with breast cancers has improved: Five-year survival has been 21 about 90% in recent years (7) partially because the increased use of adjuvant therapies such as 22 chemo-and radiotherapy. Recent advance in radiotherapy techniques substantially reduces the 23 radiation exposure to hearts during radiotherapy of breast cancers, which reduces the incidence of 24 cardiovascular diseases caused by atherosclerosis. However, even a low level of radiation exposure 25 to the hearts during contemporary radiotherapy of breast cancers still provide a deleterious impact on 26 coronary microvasculature, which is associated with the increased risk of heart failure with preserved 27 ejection fraction (HFpEF) with the mean cardiac radiation dose (12). Thus, radiation-induced 28 cardiovascular disease, especially HFpEF, emerges as the most important competing mortality risk 29 for breast cancer survivors (1). 30The effects of cardiac radiation on left ventricular (LV) diastolic function remain to be 31 poorly characterized, so far. Although the previous studies demonstrated the link between cardiac 32 radiation exposure and subsequent microvascular rarefaction in both animal models and patients with 33 breast cancer, LV diastolic function has not been assessed (9, 14). In this issue of the American 34 Journal of Physiology-Heart and Circulatory Physiology, Saiki et al. established a novel model of 35 diastolic dysfunction without reduced ejection fraction by experimental global cardiac radiation 36 exposure, in which the diastolic functional abnormalities were correlated well with the extent of 37 microvascular rarefaction. Although the current study did not assess the earliest morphological 38 changes following radiation exposure, the previous studies demonstrated that radiation primarily 39 damages the microvasculature followed by inflammatory and thrombotic changes, resulting in 40 capillary loss, and thus myocardial low tissue perfusion (14). The current study showed for the first 41 time the causal link between microvascular dysfunction and increased risk of HFpEF after breast 42 cancer radiation therapy. Interestingly, although the initial trigger is totally different, the radiation 43 exposure-related HFpEF model appears to share the same underlying mechanism with metabolic 44 risk-related human (4, 10, 16) and animal model of HFpEF (5, 13), the disturbance in the nitric oxide 45 (NO)-cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling from 46