ABSTRACT Rural dwelling adults in the US South suffer disproportionate cardiovascular disease (CVD) burden and mortality. The Appalachia and Mississippi Delta (AMD) regions are particularly at risk, embedded in the stroke, heart attack and heart failure (HF) mortality belts, where the determinants are multifactorial. Echocardiography is an ideal methodology to study CVD and determine high risk imaging phenotypes for incident heart failure owing to its ability to noninvasively assess cardiac structure and function simultaneously. Due to the excess of CVD in the AMD region, we therefore expect a high prevalence of abnormal cardiac structure and function among rural adults, but this has not been explicitly shown. The NHLBI-funded Risk Underlying Rural Areas Longitudinal (RURAL) cohort study, by assessing a broad array of phenotypic, biologic and social determinants of health represents a unique, cost-effective opportunity to implement a study to fill the gaps described, reduce excess CVD burden and achieve health equity for all Americans. The long-term goal of this proposal is to understand the burden of adverse cardiac remodeling in the absence of symptoms (i.e., Stage B HF) in the AMD region and factors contributing to it so that interventions during subclinical disease states may avert clinical HF later in life. The overall objective of this application is to establish a unique cohort, named RURAL Echo (Echocardiographic Determinants of Cardiac Structure and Function in Rural Residents). Using the infrastructure of the parent study’s mobile examination unit (MEU) – ‘a clinic on wheels’ – we will perform echocardiography on all participants at baseline to characterize cardiac structure and function using a novel artificial-intelligence (AI) echo approach. Our central hypothesis is that there is a significant burden of Stage B HF, which is associated with exposures spanning multiple domains. We will achieve our objectives through these specific aims: (Aim 1) Use AI Echo and meticulous core lab analysis to extensively characterize cardiac structure and function in the RURAL study cohort with implications for public health impact of deploying AI echo in rural settings; (Aim 2) Determine associations of AI Echo findings with known traditional biologic risk factors and comorbidities; and (Aim 3) Determine associations of AI Echo findings with emerging social determinants of health and establish if these associations are mediated by traditional biologic risk factors and comorbidities. The proposed study will provide the largest and most comprehensive echocardiographic dataset focused on rural adults, and will be the first to untangle the degree and relative importance of the association between biologic and social factors on Stage B HF among rural adults. RURAL Echo promises to yield new knowledge on rural cardiovascular health that is highly relevant to individual and US public health.