ABSTRACT: Approximately 5-10% of older adults have aortic stenosis (AS) with anticipated doubling by 2050; with no available medical therapy to slow progression, treatment is limited to aortic valve replacement (AVR). While AVR has historically been reserved for symptomatic severe AS, cardiac remodeling and irreversible injury occur before the onset of symptoms and before AS is "severe" and contribute to death and persistent heart failure (HF) symptoms/rehospitalization in up to 40% of patients 1 year after AVR, suggesting that AVR before onset of irreversible changes to the heart is likely to improve post-AVR outcomes. Fortunately, randomized strategy trials are underway to test the benefit of earlier less invasive transcatheter AVR (TAVR) before symptoms and severe AS. However, earlier TAVR isn't a panacea; beyond inherent procedural risks, this will also lead to more repeat procedures (with risks/costs) when prosthetic valves degenerate. Echocardiography and standard biomarkers (e.g., left ventricular hypertrophy [LVH], BNP) have limited sensitivity/specificity for detecting maladaptive remodeling and lack relevant biological insight. In preparation for this application, we identified circulating proteomic signatures of tissue/global cardiac phenotypes in the heart (e.g. LVH, fibrosis, systolic/diastolic function with cardiac magnetic resonance [CMR]/echo) in a group of 115 individuals across a spectrum of AS (mild to severe), defining subsets of biologically plausible and novel proteins associated with an increased risk of HF/mortality, with validation in a broader at-risk population without AS. Our central hypothesis is that myocardial remodeling/dysfunction early in the course of AS (mild-moderate; asymptomatic severe) will be accompanied by alterations in the circulating proteome pointing to known/novel pathways contributing to HF and providing an early molecular barometer for clinical surveillance and pharmacologic targeting. We will utilize state-of-the-art cardiac imaging alongside high-throughput proteomics on longitudinal samples from four cohorts of AS, including mild to severe asymptomatic AS, controls, pre- and post-TAVR sampling, and two randomized trials to: (1) develop/validate circulating proteomic signatures that reflect adverse myocardial remodeling/dysfunction relevant to AS surveillance and personalized timing of AVR; and (2) identify known/novel pathways underlying cardiac remodeling (before AVR) and cardiac recovery (after AVR) for downstream pharmacological targeting to reduce residual risk from HF. Our specific aims are: (1) identify whether proteomic signatures of myocardial remodeling/dysfunction are present early in AS before traditional clinical thresholds for intervention; (2) identify proteomic signatures of LVH regression after AVR in severe AS; and (3) determine whether proteomic signatures of cardiac health are associated with post-AVR outcomes and able to identify asymptomatic patients who benefit from prompt ...