Interplay of Myocardial Fibrosis and Cardiac TTR Amyloid in Age Related Cardiac Remodeling in MESA-Multi-Ethnic Study of Atherosclerosis

MESA 动脉粥样硬化多种族研究中心肌纤维化和心脏 TTR 淀粉样蛋白在年龄相关心脏重塑中的相互作用

• 批准号: 10589058
• 负责人: Sharmila Dorbala
• 金额: $ 137.86万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10589058
• 关键词: Acceleration; Activities of Daily Living; Aging; Amyloid; Amyloid Fibrils; Amyloid deposition; Amyloidosis; Ancillary Study; Atrial Fibrillation; Autopsy; Biological Markers; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cicatrix; Cine Magnetic Resonance Imaging; Clinical; Collagen; Data; Dementia; Detection; Development; Diffuse; Diphosphates; Disease; Disease Outcome; Early Diagnosis; Elderly; Electrocardiogram; Exposure to; Extracellular Matrix; FDA approved; Fibrosis; Functional disorder; Heart; Heart Atrium; Heart failure; High Prevalence; Hypertrophy; Image; Individual; Infiltration; Knowledge; Left; Libraries; Link; Machine Learning; Magnetic Resonance Imaging; Malignant - descriptor; Maps; Measures; Methods; Morbidity - disease rate; Multi-Ethnic Study of Atherosclerosis; Myocardial; Myocardial dysfunction; Myocardium; Older Population; Participant; Pathogenesis; Pathway interactions; Patients; Phenotype; Population; Prealbumin; Prevention strategy; Proteins; Public Health; Risk Factors; Statistical Methods; Stroke; Technetium; Technetium 99m; Techniques; Ventricular; Woman; age related; cardiac amyloidosis; clinical diagnosis; coronary fibrosis; data acquisition; design; extracellular; frailty; improved; interstitial; men; mortality; multi-ethnic; novel; novel strategies; older men; older women; phenotypic data; predictive modeling; prevent; risk stratification; β-amyloid burden; Acceleration; Activities of Daily Living; Aging; Amyloid; Amyloid Fibrils; Amyloid deposition; Amyloidosis; Ancillary Study; Atrial Fibrillation; Autopsy; Biological Markers; Cardiac; Cardiac Myocytes; Cardiovascular Diseases; Cicatrix; Cine Magnetic Resonance Imaging; Clinical; Collagen; Data; Dementia; Detection; Development; Diffuse; Diphosphates; Disease; Disease Outcome; Early Diagnosis; Elderly; Electrocardiogram; Exposure to; Extracellular Matrix; FDA approved; Fibrosis; Functional disorder; Heart; Heart Atrium; Heart failure; High Prevalence; Hypertrophy; Image; Individual; Infiltration; Knowledge; Left; Libraries; Link; Machine Learning; Magnetic Resonance Imaging; Malignant - descriptor; Maps; Measures; Methods; Morbidity - disease rate; Multi-Ethnic Study of Atherosclerosis; Myocardial; Myocardial dysfunction; Myocardium; Older Population; Participant; Pathogenesis; Pathway interactions; Patients; Phenotype; Population; Prealbumin; Prevention strategy; Proteins; Public Health; Risk Factors; Statistical Methods; Stroke; Technetium; Technetium 99m; Techniques; Ventricular; Woman; age related; cardiac amyloidosis; clinical diagnosis; coronary fibrosis; data acquisition; design; extracellular; frailty; improved; interstitial; men; mortality; multi-ethnic; novel; novel strategies; older men; older women; phenotypic data; predictive modeling; prevent; risk stratification; β-amyloid burden

Project Summary: Myocardial fibrosis is characterized by the accumulation of extracellular matrix in the myocardium and has been identified as one of the main determinants of age related cardiac remodeling. This can manifest as either increased diffuse interstitial fibrosis or focal fibrosis as a scar and lead to cardiac dysfunction. Cardiac transthyretin amyloidosis characterized by infiltration of the myocardium by misfolded transthyretin protein, on the other hand, has emerged as an important cause of accelerated remodeling leading to heart failure and CVD, and predisposing to frailty and dementia. Importantly, novel FDA approved therapies (tafamidis, inotersen) may allow treatment of cardiac amyloidosis highlighting the need for early detection. We expect this study to establish the pivotal importance of quantifying fibrosis and amyloidosis at the population level to facilitate clinical detection and orient the development of novel strategies to prevent heart failure, atrial fibrillation and complications of CVD in older adults. Therefore, our specific aims are: Aim 1a) determine the cross-sectional associations of presence as well as extent of amyloidosis measured by Tc-PYP, with extent of myocardial fibrosis measured by MRI T1 mapping at MESA Exam 7. 1b) determine cross-sectional associations of presence and extent of amyloidosis as well as fibrosis, with magnitude of cardiac remodeling defined as structural and functional alterations of the left and right heart chambers by cine MRI at MESA Exam 7.1c) construct prediction models for presence as well as for extent of both cardiac amyloidosis and progressive fibrosis at Exam 7, by combining risk factor exposure and subclinical disease trajectories based on phenotypes obtained from all MESA Exams (1-6) prior to Exam 7. In Aim 2a) we will compare the magnitude of ECV change between MESA Exams 5 and 7 in the absence versus presence, as well as extent of amyloidosis measured at Exam 7. 2b) compare the magnitude of 12-14 year changes in 4 chamber cardiac remodeling attributed to amyloidosis versus those attributed to progressive fibrosis. 2c) construct longitudinal predictive models of 12-14 year change in ECV attributed to amyloidosis versus ECV changes attributed to progressive fibrosis, using all phenotypic variables obtained from MESA Exams 1 through 5. We propose to use data acquired during 2010-2012 in 800 individuals (400 men and 400 women) as part of the MESA 5 exam. As part of this proposal, all participants will undergo a repeat MRI exam and Tc-99m-PYP at Exam 7. This study leverages the already acquired MESA phenotypic data to predict amyloidosis and malignant progressive fibrosis leading to adverse remodeling, CVD, frailty and dementia.

项目摘要： 心肌纤维化的特征是在心肌中累积细胞外基质 并被确定为年龄相关心脏重塑的主要决定因素之一。这 可以表现为增加的弥散性间质纤维化或局灶性纤维化作为疤痕，并导致 心脏功能障碍。心脏经胸蛋白淀粉样蛋白病的特征是浸润 另一方面，通过错误折叠的转染蛋白蛋白质的心肌已成为重要的 加速重塑的原因导致心力衰竭和CVD，并易于脆弱 失智。重要的是，新型FDA批准的疗法（Tafamidis，Inotersen）可能允许治疗 心脏淀粉样变性的突出了早期检测的需求。我们希望这项研究能够建立 在人群水平上量化纤维化和淀粉样变性的关键重要性以促进 临床检测并定向开发新的策略，以防止心力衰竭，房屋 老年人CVD的纤颤和并发症。因此，我们的具体目的是：目标1a） 确定存在的横截面关联以及测量的淀粉样变性程度 通过TC-PYP，通过MESA考试中的MRI T1映射测量的心肌纤维化程度7。 1b）确定存在和淀粉样变性的横断面关联以及 纤维化，其大小的心脏重塑被定义为结构和功能改变 Cine MRI在MESA考试7.1C构建预测模型的左右心腔室 在检查7中的存在以及心脏淀粉样变性和进行性纤维化的程度 通过将危险因素暴露和亚临床疾病轨迹相结合，基于表型 在考试7之前从所有MESA考试（1-6）获得。在AIM 2A中）我们将比较幅度 在不存在与存在的情况下，MESA考试5和7之间的ECV变化以及程度 在考试中测得的淀粉样变性7。2b）比较了4年的12 - 14年变化的幅度 室内心脏重塑归因于淀粉样变性，而归因于淀粉样变性 纤维化。 2C）构建ECV的12 - 14年变化的纵向预测模型 使用所有表型变量 从MESA考试1到5获得。我们建议使用2010 - 2012年期间获得的数据 800个人（400名男性和400名女性）作为MESA 5考试的一部分。作为本提案的一部分， 所有参与者将在考试中进行重复的MRI考试和TC-99M PYP。本研究利用 已经获得的台面表型数据可以预测淀粉样变性和恶性进行性 纤维化导致不良重塑，CVD，脆弱和痴呆。