Mechanisms of Arrhythmias Following Cardiac Irradiation

癌症治疗期间的辐射暴露可导致严重的心脏并发症和 初次暴露后的急性死亡和数年死亡。这些短期和长期的 随着癌症新疗法的开发和应用，并发症变得越来越重要 存活率提高了。辐射可直接损害心肌，导致冠状动脉和 瓣膜疾病，扰乱心脏神经支配，并引发心肌纤维化；这可能 随后导致收缩和舒张期功能障碍以及心房和心室 心律不齐。此外，放射治疗通常与化疗同时进行，而且它 很难理清辐射的直接影响。其背后的详细机制 放射治疗后对快速性和缓慢性心律失常的易感性尚未确定。 我们现在证明，在小鼠体内进行短期和长期的全身和心脏靶向照射 氧化应激、传导系统疾病、血清miR-34a上调、心律失常和 增加死亡率，部分是通过使用可溶于水的奥西坦尼治疗来预防的 亚砜化合物MMS350是由加州大学开发的一种辐射减震剂 匹兹堡。我们还表明，一氧化氮合酶1基因敲除(NOS1-/-)小鼠患上更多 与死亡率增加相关的严重传导性疾病，NOS1基因改变 辐射对线粒体功能和活性氧代谢的影响 NOS1基因改变辐射后对MMS350的代谢反应的途径。 我们的主要假设是NOS1和microRNAs在 通过减轻辐射对心脏和心脏传导系统的影响 氧化应激和线粒体功能障碍导致电生理重塑和 心律失常，而MMS350可以通过保护 细胞新陈代谢和能量学。为了检验这些假设，我们将使用全身和 心脏靶向照射野生型和转基因小鼠的实验研究 心脏损害导致传导性疾病和心律失常的机制 肌细胞、血管平滑肌和内皮细胞和/或自主神经系统， 并确定NOS1、MMS350和microRNAs改变损伤的机制。 这些研究将确定NOS1和microRNAs在心脏传导和 辐射暴露后的心律失常和可能缓解的试验药物治疗 这是一种挽救生命的癌症疗法的潜在致命副作用。

Radiation exposure during cancer treatment can cause significant cardiac morbidity and mortality both acutely and years after the initial exposure. These short and long-term complications are increasingly important as new therapies for cancer are developed and survival improves. Radiation can directly damage the myocardium, cause coronary artery and valvular disease, disrupt cardiac innervation and precipitate myocardial fibrosis; this can subsequently lead to systolic and diastolic dysfunction along with atrial and ventricular arrhythmias. In addition, radiation therapy is often given concomitantly with chemotherapy and it is difficult to sort out the direct effects of radiation. The detailed mechanisms underlying the susceptibility to tachy- and bradyarrhythmias following radiation therapy have not been defined. We now show that short and long-term total body and cardiac targeted irradiation in mice leads to oxidative stress, conduction system disease, serum miR-34a upregulation, arrhythmias and increased mortality which were prevented, in part, by treatment with the water soluble oxetanyl sulfoxide compound MMS350 that was developed as a radiation mitigator at the University of Pittsburgh. We also show that Nitric Oxide Synthase 1 knockout (Nos1-/-) mice develop more severe conduction disease associated with increased mortality, that Nos1 genotype alters the effects of radiation on mitochondrial function and reactive oxygen species (ROS) metabolic pathways, that Nos1 genotype alters the metabolic response to MMS350 following irradiation. Our primary hypothesis is that NOS1 and microRNAs play heretofore unrecognized roles in radiation-induced damage to the heart and cardiac conduction system by mitigating changes in oxidative stress and mitochondrial dysfunction that lead to electrophysiological remodeling and arrhythmias, and that MMS350 can mitigate the arrhythmogenic phenotype by protecting cellular metabolism and energetics. To test these hypotheses, we will use total body and cardiac targeted irradiation of wild type and genetically engineered mice to determine the mechanisms by which conduction disease and arrhythmias result from damage to cardiac myocytes, vascular smooth muscle and endothelial cells and/or the autonomic nervous system, and to determine the mechanisms by which NOS1, MMS350 and microRNAs alter the damage. These studies will define the role of Nos1 and microRNAs in cardiac conduction and arrhythmias following radiation exposure and test pharmacological therapies that may mitigate this potentially lethal side effect of a life-saving cancer therapies.