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: 10467374
• 负责人: Sharmila Dorbala
• 金额: $ 146.18万
• 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/10467374
• 关键词: 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; Foundations; Functional disorder; Heart; Heart Atrium; Heart failure; High Prevalence; Hypertrophy; Image; Individual; Infiltration; Knowledge; Lead; Left; Libraries; Link; Machine Learning; Magnetic Resonance Imaging; Malignant - descriptor; 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; base; 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.

项目概要： 心肌纤维化的特点是心肌细胞外基质的堆积 并已被确定为与年龄相关的心脏重塑的主要决定因素之一。这 可表现为弥漫性间质纤维化增加或局灶性纤维化（如疤痕）并导致 心脏功能障碍。心脏运甲状腺素蛋白淀粉样变性的特征是心肌细胞浸润 另一方面，错误折叠的转甲状腺素蛋白已成为一种重要的心肌细胞 加速重构的原因，导致心力衰竭和心血管疾病，并容易导致虚弱和 失智。重要的是，FDA 批准的新型疗法（tafamidis、inotersen）可能允许治疗 心脏淀粉样变性的发生凸显了早期检测的必要性。我们期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至关重要 临床检测并指导开发预防心力衰竭、心房疾病的新策略 老年人的颤动和心血管疾病并发症。因此，我们的具体目标是：目标 1a) 确定所测量的淀粉样变性的存在和程度的横截面关联 通过 Tc-PYP，并通过 MESA 考试 7 中的 MRI T1 映射测量心肌纤维化程度。 1b) 确定淀粉样变性的存在和程度的横截面关联以及 纤维化，心脏重塑的程度定义为结构和功能的改变 MESA 考试 7.1c 中通过电影 MRI 测量左心室和右心室构建预测模型 检查 7 时是否存在心脏淀粉样变性和进行性纤维化以及其程度， 通过结合危险因素暴露和基于表型的亚临床疾病轨迹 在考试 7 之前从所有 MESA 考试 (1-6) 获得。在目标 2a) 中，我们将比较大小 MESA 考试 5 和 7 之间缺席与出席情况下的 ECV 变化以及程度 7. 2b) 中测量的淀粉样变性比较 4 中 12-14 年变化的幅度 淀粉样变性引起的心室重构与进行性淀粉样变性引起的心室重构 纤维化。 2c) 构建 ECV 12-14 年变化的纵向预测模型，归因于 使用所有表型变量比较淀粉样变性与进行性纤维化导致的 ECV 变化 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 MESA 5 考试有 800 人（400 名男性和 400 名女性）参加。作为该提案的一部分， 所有参与者都将在考试 7 时接受重复 MRI 检查和 Tc-99m-PYP。这项研究利用 已获得的 MESA 表型数据可预测淀粉样变性和恶性进展 纤维化导致不良重塑、心血管疾病、虚弱和痴呆。