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

项目总结： 心肌纤维化的特征是细胞外基质在心肌内积聚。 已被认为是年龄相关性心脏重构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形成疤痕，并导致 心脏功能不全。心脏转甲状腺素淀粉样变性的特点是 另一方面，通过错误折叠的转甲状腺素蛋白引起的心肌已经成为一种重要的 导致心力衰竭和心血管疾病的加速重塑的原因，并容易虚弱和 痴呆症。重要的是，FDA批准的新疗法(他法米迪、诺特森)可能会允许治疗 心脏淀粉样变性突出了早期发现的必要性。我们希望这项研究能够确定 在人群水平上量化纤维化和淀粉样变性的关键重要性 临床检测和定向开发预防心力衰竭、心房的新策略 老年人心血管疾病的纤颤和并发症。因此，我们的具体目标是：目标1a) 确定存在的横断面关联以及测量的淀粉样变性的程度 TC-PYP，在MESA检查7时用MRI T1标测心肌纤维化程度。 1b)确定淀粉样变性的存在和程度以及 纤维化，心脏重塑的程度定义为心脏结构和功能的改变 在MESA检查中使用电影磁共振成像的左右心腔构建预测模型 对于检查7中心脏淀粉样变性和进行性纤维化的存在和程度， 通过结合风险因素暴露和基于表型的亚临床疾病轨迹 来自考试7之前的所有MESA考试(1-6)。在目标2a)中，我们将比较 MESA检查5和7在缺席与在场之间的ECV变化，以及范围 在检查7。2b中测量的淀粉样变性)比较了4年中12-14年变化的幅度。 淀粉样变性与进行性心脏重构的对比研究 纤维化症。2C)建立12-14年ECV变化的纵向预测模型，归因于 使用所有表型变量的淀粉样变性与进行性纤维化所致的ECV变化 来自MESA考试1至5。我们建议使用2010-2012年间获得的数据 800人(400名男性和400名女性)作为MESA 5考试的一部分。作为这项提议的一部分， 所有参与者都将在第7次检查时接受重复的MRI检查和Tc-99m-PYP检查。 已经获得的预测淀粉样变性和恶性进展的MESA表型数据 纤维化导致不良重塑、心血管疾病、虚弱和痴呆症。

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.