Mechanisms of Arrhythmias Following Cardiac Irradiation

癌症治疗期间的辐射暴露可导致显著的心脏病发病率， 急性死亡率和初次接触后数年的死亡率。这些短期和长期 随着癌症新疗法的开发，并发症越来越重要， 生存改善。放射线可直接损伤心肌，引起冠状动脉病变， 心脏瓣膜病，破坏心脏神经支配和沉淀心肌纤维化;这可以 随后导致收缩和舒张功能障碍沿着心房和心室 心律不齐此外，放射治疗通常与化疗同时进行， 很难弄清辐射的直接影响。详细的机制背后的 放射治疗后对快速和缓慢心律失常的敏感性尚未确定。 我们现在表明，短期和长期全身和心脏靶向照射小鼠导致 氧化应激、传导系统疾病、血清miR-34 a上调、心律失常和 死亡率增加，部分通过用水溶性氧杂环丁烷治疗来预防 亚砜化合物MMS 350，是在美国加州大学开发的一种辐射缓解剂。 匹兹堡我们还表明一氧化氮合酶1敲除（Nos 1-/-）小鼠发育得更多 严重的传导疾病与死亡率增加相关，Nos 1基因型改变了 辐射对线粒体功能和活性氧代谢的影响 Nos 1基因型改变了辐射后对MMS 350的代谢反应。 我们的主要假设是，NOS 1和microRNA发挥迄今尚未认识的作用， 通过减轻心脏和心脏传导系统的变化， 氧化应激和线粒体功能障碍，导致电生理重塑， MMS 350可以通过保护心律失常来减轻致心律失常表型， 细胞代谢和能量学。为了验证这些假设，我们将使用全身和 心脏靶向照射野生型和基因工程小鼠，以确定 传导疾病和心律失常的机制是由心脏损害引起的。 肌细胞、血管平滑肌和内皮细胞和/或自主神经系统， 并探讨NOS 1、MMS 350和microRNA改变损伤的机制。 这些研究将确定Nos 1和microRNA在心脏传导中的作用， 辐射暴露后的心律失常和试验药物治疗， 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.