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

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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.