Targeting the Arrhythmogenic Sources of Human Atrial Fibrillation

针对人类心房颤动的心律失常根源

基本信息

批准号：
10620785
负责人：
Vadim V Fedorov
金额：
$ 67.09万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620785
关键词：
3-Dimensional Ablation Affect Age Animals Arrhythmia Atrial Fibrillation Automobile Driving Cells Characteristics Clinical Clinical Research Complex Computer Models Data Development Diabetes Mellitus Disease Electrodes Extracellular Matrix Fibroblasts Fibrosis Fingerprint Funding Genes Genetic Fingerprintings Goals Heart Heart Atrium Heart Research Heart failure Histology Hospitalization Human Hypertension Image Individual Inflammatory Left Machine Learning Macrophage Magnetic Resonance Imaging Maps Microanatomy Modeling Molecular Molecular Genetics Molecular Profiling Morbidity - disease rate Multimodal Imaging Obesity Optics PET/CT scan Patients Positron-Emission Tomography Proteins Publishing Recording of previous events Research Resolution Right atrial structure Risk Factors Role Signal Pathway Source Stroke Structure Surface Technology Testing Therapeutic Intervention Three-Dimensional Imaging Training Translational Research United States Validation X-Ray Computed Tomography aging population bench to bedside canine model clinical imaging comorbidity contrast enhanced extracellular functional disability imaging approach in vivo machine learning algorithm multimodality novel periostin personalized medicine pharmacologic pre-clinical programs sex side effect three dimensional structure transcriptomics translational framework translational pipeline translational study

项目摘要

PROJECT SUMMARY Atrial fibrillation (AF) is a leading cause of stroke and an increasingly prevalent arrhythmia in the United States due to an aging population with predisposing comorbidities (e.g. heart failure, obesity, diabetes, high blood pressure, etc.). Although there have been great technological advances in the treatment of AF, current therapies still remain insufficient due to limited understanding of the mechanisms that drive and maintain AF. Clinical studies lack reliable functional and structural mapping approaches necessary to resolve the patient-specific arrhythmogenic transmural substrate, due to the highly complex 3D structure of the human atria. Subsequently, there remains a significant debate around the mechanisms driving AF, the cause of these drivers, and how best to locate and treat these patient-specific drivers that can occur in both left and right atrial chambers. Therefore, our proposal aims to develop a novel, paradigm-shifting translational framework that uses ex-vivo to in-vivo 3D multimodal imaging approaches to accurately define disease- and sex-specific bi-atrial arrhythmogenic substrates of AF drivers, so that we can elucidate the “fingerprint” features of AF drivers. Our preliminary data led us to hypothesize that disease- and sex-specific fibrotic cellular and extracellular remodeling is heterogeneously present in one or more LA and RA transmural layers (sub-epi, intramural, and sub-endo) and can form arrhythmogenic substrates for localized reentrant AF drivers and represent personalized targets for AF treatment. We will test this hypothesis, directly in explanted human atria and a preclinical animal AF model, by integrating transmural optical mapping, clinical multi-electrode mapping, 3D MRI and PET/CT imaging, and proteo-transcriptomic analyses to define chamber- and disease-specific signaling pathways and structural- molecular-genetic fingerprints of arrhythmogenic AF driver substrates. The validated AF driver substrate fingerprints will be used to train machine learning algorithms to define patient-specific targets in persistent AF patients for either substrate modulating ablation of reentrant tracks (SMART) or anti-fibrotic therapeutic interventions. This translational research is a critical step toward the development of new personalized, mechanism-based, and sex-specific AF treatments whereby driver substrates can be accurately defined, targeted, and successfully treated to cure the most common arrhythmia in the United States.

项目概要心房颤动 (AF) 是美国中风和日益流行的心律失常的主要原因由于人口老龄化和易患合并症（例如心力衰竭、肥胖、糖尿病、高血压尽管房颤的治疗已经取得了巨大的技术进步，但目前的治疗方法由于对驱动和维持 AF 的临床机制的了解有限，仍然存在不足。研究缺乏解决患者特定问题所必需的可靠的功能和结构图谱方法由于人类心房高度复杂的 3D 结构，导致心律失常的透壁基质。关于房颤的驱动机制、这些驱动因素的原因以及如何最好地进行治疗，仍然存在着重大争论。定位并治疗这些可能发生在左心房和右心房的患者特定驱动因素。因此，我们的建议旨在开发一种新颖的、范式转变的翻译框架，利用体外体内 3D 多模态成像方法可准确定义疾病和性别特异性双心房 AF驱动器的致心律失常底物，使我们能够阐明AF驱动器的“指纹”特征。初步数据引导我们解决疾病和性别特异性的纤维化细胞和细胞外重塑异质地存在于一层或多层 LA 和 RA 透壁层（外壁下、壁内和内膜下）中，并且可以形成局部折返性房颤驱动因素的致心律失常底物，并代表房颤的个性化目标我们将直接在移植的人类心房和临床前动物 AF 模型中测试这一假设。反式积分壁画光学测绘、临床多电极测绘、3D MRI 和 PET/CT 成像，以及蛋白质转录组分析可定义腔室和疾病特异性信号传导途径和结构致心律失常 AF 驱动底物的分子遗传指纹经过验证的 AF 驱动底物。指纹将用于训练机器学习算法，以定义持续性 AF 中的患者特定目标接受基底调节折返轨迹消融 (SMART) 或抗纤维化治疗的患者这项转化研究是开发新的个性化干预措施的关键一步。基于机制和性别特异性的 AF 治疗，以便可以准确定义驱动基板，有针对性，并成功治疗治愈了美国最常见的心律失常。