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会导致严重的心脏发病率，并且急性死亡和初次接触后的几年。这些短期和长期随着开发癌症的新疗法，并发症变得越来越重要，并且生存改善。辐射会直接损害心肌，引起冠状动脉和瓣膜疾病，干扰心脏神经并沉淀心肌纤维化；这可以随后导致收缩和舒张功能障碍以及心房和心室心律不齐。此外，放射治疗通常与化学疗法同时同时进行很难整理出辐射的直接影响。详细机制尚未确定放射治疗后对速度和心律不齐的敏感性。我们现在表明，小鼠铅的短期和长期总体和心脏靶向辐照氧化应激，传导系统疾病，血清miR-34a上调，心律不齐和死亡率提高，部分通过用水溶性氧甲酰治疗来阻止的死亡率硫酸化合物MMS350是在大学的辐射缓解剂中开发的匹兹堡。我们还表明一氧化氮合酶1敲除（NOS1 - / - ）小鼠发展更多与死亡率增加有关的严重传导疾病，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基因型在辐照后改变了对MMS350的代谢反应。我们的主要假设是NOS1和MicroRNA在迄今未识别的角色中扮演辐射引起对心脏和心脏传导系统的损害，通过减轻变化氧化应激和线粒体功能障碍，导致电生理重塑和心律不齐，MMS350可以通过保护来减轻心律不齐的表型细胞代谢和能量学。为了检验这些假设，我们将使用总体和心脏靶向野生型和基因工程小鼠的辐照，以确定受损对心脏导致传导疾病和心律不齐的机制心肌细胞，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改变损害的机制。这些研究将定义NOS1和microRNA在心脏传导中的作用辐射暴露和测试药理疗法后的心律失常，可能减轻挽救生命的癌症疗法的这种潜在致命的副作用。