Mechanisms of Arrhythmias Following Cardiac Irradiation

心脏照射后心律失常的机制

基本信息

批准号：
10397541
负责人：
Barry London
金额：
$ 47.29万
依托单位：
UNIVERSITY OF IOWA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10397541
关键词：
Acute Affect Arrhythmia Autonomic nervous system Biological Markers Bradyarrhythmias Calcium Cardiac Cardiac Myocytes Cardiac conduction system Chronic Coronary artery Data Disease Distant Echocardiography Electrocardiogram Electrophysiology (science)Endothelial Cells Endothelium Energy Metabolism Exposure to External Beam Radiation Therapy Fibrosis Functional disorder Genetically Engineered Mouse Genotype Heart Heart Atrium Histology Ion Channel Ionizing radiation Ischemia Knock-out Knockout Mice Lead Life Link Malignant neoplasm of thorax Measures Mechanics Metabolic Metabolic Pathway Metabolism MicroRNAs Mitochondria Morbidity - disease rate Morphology Mus Myocardium Nitric Oxide Synthase Type I Oxidative Stress Pathology Pharmacology Phenotype Play Post-Translational Protein Processing Predisposition Production Radiation Radiation exposure Radiation induced damage Radiation therapy Reactive Oxygen Species Risk Role Savings Serum Smooth Muscle Myocytes Sudden Death Sulfoxide System Tachyarrhythmias Telemetry Testing Time Tissues Universities Up-Regulation Vascular Smooth Muscle Ventricular Arrhythmia Water Whole-Body Irradiation cancer therapy chemotherapy coronary fibrosis exosome experimental study heart innervation improved irradiation mRNA Expression mitochondrial dysfunction molecular marker mortality nerve supply novel therapeutics overexpression prevent protective effect protein expression radiation effect radiation mitigator response side effect voltage clamp

项目摘要

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.

癌症治疗期间的辐射暴露可导致显着的心脏病发病率和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新的癌症疗法的开发和应用，并发症变得越来越重要生存改善。放射线可直接损伤心肌，引起冠状动脉损伤瓣膜疾病，扰乱心脏神经支配并加速心肌纤维化；这个可以随后导致收缩和舒张功能障碍以及心房和心室功能障碍心律失常。此外，放射治疗通常与化学疗法同时进行。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心律失常和缓慢性心律失常的易感性尚未确定。我们现在表明，对小鼠进行短期和长期全身和心脏靶向照射会导致氧化应激、传导系统疾病、血清 miR-34a 上调、心律失常和死亡率增加，部分通过水溶性氧杂环丁基处理得以预防亚砜化合物 MMS350，是英国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 (Nos1-/-) 小鼠发育更多与死亡率增加相关的严重传导疾病，Nos1 基因型改变了辐射对线粒体功能和活性氧（ROS）代谢的影响途径，Nos1 基因型改变了辐射后对 MMS350 的代谢反应。我们的主要假设是 NOS1 和 microRNA 在通过减轻辐射对心脏和心脏传导系统的损害氧化应激和线粒体功能障碍导致电生理重塑和心律失常，并且 MMS350 可以通过保护来减轻致心律失常表型细胞代谢和能量学。为了检验这些假设，我们将使用全身和对野生型和基因工程小鼠进行心脏靶向照射，以确定心脏损伤导致传导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 microRNA 改变损伤的机制。这些研究将明确 Nos1 和 microRNA 在心脏传导和心脏传导中的作用辐射暴露后的心律失常并测试可以缓解的药物疗法这种可能致命的副作用是一种挽救生命的癌症疗法。