Project Abstract Heart failure (HF) with preserved ejection fraction (HFpEF) is a major public health concern that disproportionately affects the elderly and currently has no effective therapy. Accumulating evidence suggests that myocardial deposition of misfolded transthyretin proteins (ATTR) increases with age and is responsible for 13-18% of HFpEF in late life. ATTR cardiac amyloidosis (CA) is one of the most-deadly forms of HF with a median survival of 25-41 months. The diagnosis of ATTR-CA has commonly been delayed, often by several years, because of the need for invasive endocardial biopsy for diagnosis and lack of urgency due to limited therapeutic options. This has changed recently. ATTR CA can now be diagnosed non-invasively using 99mtechnetium pyrophosphate (99mTc-PYP) imaging, and recent therapeutic breakthroughs (e.g., tafamidis, inotersen, patisiran) have improved survival, alleviated symptoms, and reduced HF hospitalizations. However, lack of knowledge regarding the early changes in cardiac structure, function, and circulating biomarkers that reflect myocardial ATTR deposition, and their prognostic relevance in elderly persons free of HF are key barriers to effectively harnessing recent diagnostic and therapeutic breakthroughs to treat and prevent this important cause of HFpEF. Over the past 8 years, we have been building a unique database detailing longitudinal changes in cardiac structure and function over 5 years in >4,000 elderly participants (age 70-95 years) in the largely biracial Atherosclerosis Risk in Communities (ARIC) cohort study. We now aim to leverage this rich resource, in addition to serial clinical and circulating biomarker data over 25 years, to define the prevalence, predictors, and prognostic importance of incidentally detected late-life cardiac ATTR deposits. We will perform 99mTc-PYP SPECT imaging in 900 ARIC participants with either prevalent HFpEF (n=300) or asymptomatic cardiac remodeling/dysfunction (n=600). Our specific aims are to: 1) Define antecedent alterations in cardiac structure, function, and circulating biomarkers that discriminate late-life HFpEF with compared to without ATTR-CA. ; 2) Determine the predictors and prognostic relevance of ATTR-CA in elderly persons without HF but with cardiac remodeling/dysfunction; and 3) Define the extent to which novel candidate proteins and protein networks in mid- and late-life predict ATTR-CA in late-life. At the completion of this project, we will have defined the cardiac changes that antecede and predict HF from ATTR-CA, established the prognostic importance of asymptomatic ATTR-CA in late life, and identified novel circulating biomarkers of ATTR-CA. These findings will facilitate identification of persons at high risk to screen for ATTR-CA to facilitate HF treatment and, possibly, prevention. The results of these studies are likely to identify novel therapeutic targets to transform the management of ATTR-CA.